@article {1128, title = {Age and cystatin C in healthy adults: a collaborative study.}, journal = {Nephrol Dial Transplant}, volume = {25}, year = {2010}, month = {2010 Feb}, pages = {463-9}, abstract = {

BACKGROUND: Kidney function declines with age, but a substantial portion of this decline has been attributed to the higher prevalence of risk factors for kidney disease at older ages. The effect of age on kidney function has not been well described in a healthy population across a wide age spectrum.

METHODS: The authors pooled individual-level cross-sectional data from 18 253 persons aged 28-100 years in four studies: the Cardiovascular Health Study; the Health, Aging and Body Composition Study; the Multi-Ethnic Study of Atherosclerosis and the Prevention of Renal and Vascular End-Stage Disease cohort. Kidney function was measured by cystatin C. Clinical risk factors for kidney disease included diabetes, hypertension, obesity, smoking, coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

RESULTS: Across the age range, there was a strong, non-linear association of age with cystatin C concentration. This association was substantial, even among participants free of clinical risk factors for kidney disease; mean cystatin C levels were 46\% higher in participants 80 and older compared with those <40 years (1.06 versus 0.72 mg/L, P < 0.001). Participants with one or more risk factors had higher cystatin C concentrations for a given age, and the age association was slightly stronger (P < 0.001 for age and risk factor interaction).

CONCLUSIONS: There is a strong, non-linear association of age with kidney function, even in healthy individuals. An important area for research will be to investigate the mechanisms that lead to deterioration of kidney function in apparently healthy persons.

}, keywords = {Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Cystatin C, Humans, Kidney, Middle Aged, Reference Values}, issn = {1460-2385}, doi = {10.1093/ndt/gfp474}, author = {Odden, Michelle C and Tager, Ira B and Gansevoort, Ron T and Bakker, Stephan J L and Katz, Ronit and Fried, Linda F and Newman, Anne B and Canada, Robert B and Harris, Tamara and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G} } @article {1348, title = {Antihypertensive medication use and change in kidney function in elderly adults: a marginal structural model analysis.}, journal = {Int J Biostat}, volume = {7}, year = {2011}, month = {2011}, pages = {Article 34}, abstract = {

BACKGROUND: The evidence for the effectiveness of antihypertensive medication use for slowing decline in kidney function in older persons is sparse. We addressed this research question by the application of novel methods in a marginal structural model.

METHODS: Change in kidney function was measured by two or more measures of cystatin C in 1,576 hypertensive participants in the Cardiovascular Health Study over 7 years of follow-up (1989-1997 in four U.S. communities). The exposure of interest was antihypertensive medication use. We used a novel estimator in a marginal structural model to account for bias due to confounding and informative censoring.

RESULTS: The mean annual decline in eGFR was 2.41 {\textpm} 4.91 mL/min/1.73 m(2). In unadjusted analysis, antihypertensive medication use was not associated with annual change in kidney function. Traditional multivariable regression did not substantially change these estimates. Based on a marginal structural analysis, persons on antihypertensives had slower declines in kidney function; participants had an estimated 0.88 (0.13, 1.63) ml/min/1.73 m(2) per year slower decline in eGFR compared with persons on no treatment. In a model that also accounted for bias due to informative censoring, the estimate for the treatment effect was 2.23 (-0.13, 4.59) ml/min/1.73 m(2) per year slower decline in eGFR.

CONCLUSION: In summary, estimates from a marginal structural model suggested that antihypertensive therapy was associated with preserved kidney function in hypertensive elderly adults. Confirmatory studies may provide power to determine the strength and validity of the findings.

}, keywords = {Aged, Antihypertensive Agents, Cystatin C, Data Interpretation, Statistical, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney, Longitudinal Studies, Male, Models, Statistical}, issn = {1557-4679}, doi = {10.2202/1557-4679.1320}, author = {Odden, Michelle C and Tager, Ira B and van der Laan, Mark J and Delaney, Joseph A C and Peralta, Carmen A and Katz, Ronit and Sarnak, Mark J and Psaty, Bruce M and Shlipak, Michael G} } @article {1277, title = {Longitudinal association of depressive symptoms with rapid kidney function decline and adverse clinical renal disease outcomes.}, journal = {Clin J Am Soc Nephrol}, volume = {6}, year = {2011}, month = {2011 Apr}, pages = {834-44}, abstract = {

BACKGROUND AND OBJECTIVES: Depression is a risk indicator for adverse outcomes in dialysis patients, but its prognostic impact in individuals who are not yet on dialysis is unknown. This study examines whether depressive symptoms are longitudinally associated with renal function decline, new-onset chronic kidney disease (CKD), ESRD, or hospitalization with acute kidney injury (AKI).

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Depressive symptoms were measured in a longitudinal cohort study with the 10-item Centers for Epidemiologic Studies Depression scale using a previously validated cut-off value (>=8). CKD at study entry and during follow-up was defined as an estimated GFR (eGFR) < 60 ml/min per m(2). Outcomes were rapid decline in eGFR (>3 ml/min per m(2) per year), new-onset CKD, ESRD (U.S. Renal Data System-based), and AKI (based on adjudicated medical record review). The median follow-up duration was 10.5 years.

RESULTS: Depressed participants (21.2\%) showed a higher prevalence of CKD at baseline compared with nondepressed participants in multivariable analysis. Depression was associated with a subsequent risk of rapid decline in eGFR, incident ESRD, and AKI, but not incident CKD in unadjusted models. In multivariable analyses, only associations of depressive symptoms with AKI remained significant.

CONCLUSIONS: Elevated depressive symptoms are associated with subsequent adverse renal disease outcomes. The depression-related elevated risk of AKI was independent of traditional renal disease risk factors and may in part be explained by the predictive value of depression for acute coronary syndromes and heart failure hospitalizations that can be complicated by AKI.

}, keywords = {Acute Kidney Injury, Aged, Chronic Disease, Cohort Studies, Comorbidity, Depression, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Diseases, Longitudinal Studies, Male}, issn = {1555-905X}, doi = {10.2215/CJN.03840510}, author = {Kop, Willem J and Seliger, Stephen L and Fink, Jeffrey C and Katz, Ronit and Odden, Michelle C and Fried, Linda F and Rifkin, Dena E and Sarnak, Mark J and Gottdiener, John S} } @article {1395, title = {Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars.}, journal = {J Am Geriatr Soc}, volume = {60}, year = {2012}, month = {2012 Jul}, pages = {1201-7}, abstract = {

OBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians.

DESIGN: Retrospective analysis of prospectively collected data.

SETTING: Community.

PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.

MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.

RESULTS: Mean age of the participants was 85, 64\% were female, 66\% had hypertension, 14\% had diabetes mellitus, and 39\% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U-shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (>= 75 mL/min per 1.73 m(2) ) and lowest (<= 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95\% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95\% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95\% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ).

CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U-shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) .

}, keywords = {Aged, 80 and over, Analysis of Variance, Cardiovascular Diseases, Chi-Square Distribution, Creatinine, Cystatin C, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney Diseases, Male, Prevalence, Proportional Hazards Models, Retrospective Studies, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2012.04046.x}, author = {Shastri, Shani and Katz, Ronit and Rifkin, Dena E and Fried, Linda F and Odden, Michelle C and Peralta, Carmen A and Chonchol, Michel and Siscovick, David and Shlipak, Michael G and Newman, Anne B and Sarnak, Mark J} } @article {5854, title = {Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study.}, journal = {Ann Epidemiol}, volume = {23}, year = {2013}, month = {2013 Mar}, pages = {106-11}, abstract = {

PURPOSE: To determine if the associations among established risk factors and reduced kidney function vary by age.

METHODS: We pooled cross-sectional data from 14,788 nondiabetics aged 40 to 100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.

RESULTS: Hypertension and low high-density lipoprotein (HDL) cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95\% confidence interval [CI], 0.1, 4.4), 5.1 (95\% CI, 4.1, 6.1), and 6.9 (95\%~CI, 3.0, 10.4) mL/min/1.73 m(2) lower eGFR in participants 40 to 59, 60 to 79, and at least 80~years, respectively (P for interaction < .001). The association of low HDL cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (95\% CI, 3.5, 6.3), 7.1 (95\% CI, 6.0, 8.3), 8.9 (95\% CI, 5.4, 11.9) mL/min/1.73 m(2) (P for interaction < .001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.

CONCLUSIONS: Hypertension, obesity, smoking, and low HDL cholesterol are modestly associated with reduced kidney function in nondiabetics. The associations of hypertension and HDL cholesterol with reduced kidney function seem to be stronger in older adults.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Aging, Causality, Cholesterol, LDL, Cohort Studies, Comorbidity, Cross-Sectional Studies, Cystatin C, Female, Humans, Hypertension, Kidney Function Tests, Male, Netherlands, Obesity, Prevalence, Renal Insufficiency, Chronic, Risk Factors, Smoking, United States}, issn = {1873-2585}, doi = {10.1016/j.annepidem.2012.12.004}, author = {Odden, Michelle C and Tager, Ira B and Gansevoort, Ron T and Bakker, Stephan J L and Fried, Linda F and Newman, Anne B and Katz, Ronit and Satterfield, Suzanne and Harris, Tamara B and Sarnak, Mark J and Siscovick, David and Shlipak, Michael G} } @article {6136, title = {Kidney function and prevalent and incident frailty.}, journal = {Clin J Am Soc Nephrol}, volume = {8}, year = {2013}, month = {2013 Dec}, pages = {2091-9}, abstract = {

BACKGROUND AND OBJECTIVES: Kidney disease is associated with physiologic changes that may predispose to frailty. This study sought to investigate whether lower levels of kidney function were associated with prevalent or incident frailty in Cardiovascular Health Study (CHS) participants.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: CHS enrolled community-dwelling adults age >=65 years between 1989-1990 and 1992-1993. To examine prevalent frailty, included were 4150 participants without stroke, Parkinson disease, prescribed medications for Alzheimer disease or depression, or severely impaired cognition. To examine incident frailty, included were a subset of 3459 participants without baseline frailty or development of exclusion criteria during follow-up. The primary predictor was estimated GFR (eGFR) calculated using serum cystatin C (eGFR(cys)). Secondary analyses examined eGFR using serum creatinine (eGFR(SCr)). Outcomes were prevalent frailty and incident frailty at 4 years of follow-up. Frailty was ascertained on the basis of weight loss, exhaustion, weakness, slowness, and low physical activity.

RESULTS: The mean age was 75 years and the median eGFR(cys) was 73 ml/min per 1.73 m(2). Among participants with an eGFR(cys) <45 ml/min per 1.73 m(2), 24\% had prevalent frailty. In multivariable analysis and compared with eGFR(cys) >=90 ml/min per 1.73 m(2), eGFR(cys) categories of 45-59 (odds ratio [OR], 1.80; 95\% confidence interval [CI], 1.17 to 2.75) and 15-44 (OR, 2.87; 95\% CI, 1.72 to 4.77) were associated with higher odds of frailty, whereas 60-75 (OR, 1.14; 95\% CI, 0.76 to 1.70) was not. In multivariable analysis, eGFR(cys) categories of 60-75 (incidence rate ratio [IRR], 1.72; 95\% CI, 1.07 to 2.75) and 15-44 (IRR, 2.28; 95\% CI, 1.23 to 4.22) were associated with higher incidence of frailty whereas 45-59 (IRR, 1.53; 95\% CI, 0.90 to 2.60) was not. Lower levels of eGFR(SCr) were not associated with higher risk of prevalent or incident frailty.

CONCLUSIONS: In community-dwelling elders, lower eGFR(cys) was associated with a higher risk of prevalent and incident frailty whereas lower eGFR(SCr) was not. These findings highlight the importance of considering non-GFR determinants of kidney function.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, Creatinine, Cross-Sectional Studies, Cystatin C, Fatigue, Female, Frail Elderly, Geriatric Assessment, Glomerular Filtration Rate, Humans, Incidence, Independent Living, Kidney, Kidney Diseases, Logistic Models, Male, Motor Activity, Multivariate Analysis, Muscle Weakness, Odds Ratio, Phenotype, Prevalence, Prospective Studies, Risk Factors, Time Factors, United States, Weight Loss}, issn = {1555-905X}, doi = {10.2215/CJN.02870313}, author = {Dalrymple, Lorien S and Katz, Ronit and Rifkin, Dena E and Siscovick, David and Newman, Anne B and Fried, Linda F and Sarnak, Mark J and Odden, Michelle C and Shlipak, Michael G} } @article {6364, title = {Kidney function and cognitive health in older adults: the Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {180}, year = {2014}, month = {2014 Jul 01}, pages = {68-75}, abstract = {

Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C-based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m(2) had a 0.64 (95\% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95\% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m(2). Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m(2) had fewer cognitive impairment-free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m(2), independent of confounders and mediating cardiovascular events (mean difference = -0.44, 95\% confidence interval: -0.62, -0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.

}, keywords = {Aged, Cardiovascular Diseases, Cognition, Cognition Disorders, Cystatin C, Female, Glomerular Filtration Rate, Health Status, Humans, Kidney, Kidney Diseases, Male, Neuropsychological Tests}, issn = {1476-6256}, doi = {10.1093/aje/kwu102}, author = {Darsie, Brendan and Shlipak, Michael G and Sarnak, Mark J and Katz, Ronit and Fitzpatrick, Annette L and Odden, Michelle C} } @article {6363, title = {Prognostic implications of microvascular and macrovascular abnormalities in older adults: cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Dec}, pages = {1495-502}, abstract = {

BACKGROUND: Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.

METHODS: This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999-2009).

RESULTS: At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95\% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease.

CONCLUSIONS: Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Aging, Ankle Brachial Index, Disability Evaluation, Electrocardiography, Female, Follow-Up Studies, Forecasting, Humans, Life Expectancy, Magnetic Resonance Imaging, Male, Microcirculation, Prognosis, Prospective Studies, Risk Factors, Vascular Malformations}, issn = {1758-535X}, doi = {10.1093/gerona/glu074}, author = {Kim, Dae Hyun and Grodstein, Francine and Newman, Anne B and Chaves, Paulo H M and Odden, Michelle C and Klein, Ronald and Sarnak, Mark J and Patel, Kushang V and Lipsitz, Lewis A} } @article {6588, title = {Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {237}, year = {2014}, month = {2014 Nov}, pages = {336-42}, abstract = {

OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.

METHODS: Participants (n~=~4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).

RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction~=~0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95\% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).

CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.

}, keywords = {Aged, Aged, 80 and over, Blood Pressure, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Diabetes Complications, Diabetes Mellitus, Female, Humans, Inflammation, Kidney, Kidney Diseases, Lipids, Male, Natriuretic Peptide, Brain, Obesity, Peptide Fragments, Risk Factors}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2014.09.012}, author = {Odden, Michelle C and Shlipak, Michael G and Whitson, Heather E and Katz, Ronit and Kearney, Patricia M and deFilippi, Chris and Shastri, Shani and Sarnak, Mark J and Siscovick, David S and Cushman, Mary and Psaty, Bruce M and Newman, Anne B} } @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 {6398, title = {Systolic and diastolic blood pressure, incident cardiovascular events, and death in elderly persons: the role of functional limitation in the Cardiovascular Health Study.}, journal = {Hypertension}, volume = {64}, year = {2014}, month = {2014 Sep}, pages = {472-80}, abstract = {

Whether limitation in the ability to perform activities of daily living (ADL) or gait speed can identify elders in whom the association of systolic and diastolic blood pressure (DBP) with cardiovascular events (CVDs) and death differs is unclear. We evaluated whether limitation in ADL or gait speed modifies the association of systolic blood pressure or DBP with incident CVD (n=2358) and death (n=3547) in the Cardiovascular Health Study. Mean age was 78{\textpm}5 and 21\% reported limitation in >=1 ADL. There were 778 CVD and 1289 deaths over 9 years. Among persons without and those with ADL limitation, systolic blood pressure was associated with incident CVD: hazard ratio [HR] (per 10-mm Hg increase) 1.08 (95\% confidence interval, 1.03, 1.13) and 1.06 (0.97, 1.17), respectively. ADL modified the association of DBP with incident CVD. Among those without ADL limitation, DBP was weakly associated with incident CVD, HR 1.04 (0.79, 1.37) for DBP >80, compared with <65 mm Hg. Among those with ADL limitation, DBP was inversely associated with CVD: HR 0.65 (0.44, 0.96) for DBP 66 to 80 mm Hg and HR 0.49 (0.25, 0.94) for DBP >80, compared with DBP <=65. Among people with ADL limitation, a DBP of 66 to 80 had the lowest risk of death, HR 0.72 (0.57, 0.91), compared with a DBP of <=65. Associations did not vary by 15-feet walking speed. ADL can identify elders in whom diastolic hypotension is associated with higher cardiovascular risk and death. Functional status, rather than chronologic age alone, should inform design of hypertension trials in elders.

}, keywords = {Activities of Daily Living, African Continental Ancestry Group, Aged, Aged, 80 and over, Blood Pressure, Cardiovascular Diseases, Diastole, European Continental Ancestry Group, Female, Follow-Up Studies, Gait, Heart Rate, Humans, Incidence, Longitudinal Studies, Male, Risk Factors, Survival Rate, Systole}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.114.03831}, author = {Peralta, Carmen A and Katz, Ronit and Newman, Anne B and Psaty, Bruce M and Odden, Michelle C} } @article {6852, title = {Microvascular and Macrovascular Abnormalities and Cognitive and Physical Function in Older Adults: Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 Sep}, pages = {1886-93}, abstract = {

OBJECTIVES: To evaluate and compare the associations between microvascular and macrovascular abnormalities and cognitive and physical function

DESIGN: Cross-sectional analysis of the Cardiovascular Health Study (1998-1999).

SETTING: Community.

PARTICIPANTS: Individuals with available data on three or more of five microvascular abnormalities (brain, retina, kidney) and three or more of six macrovascular abnormalities (brain, carotid artery, heart, peripheral artery) (N = 2,452; mean age 79.5).

MEASUREMENTS: Standardized composite scores derived from three cognitive tests (Modified Mini-Mental State Examination, Digit-Symbol Substitution Test, Trail-Making Test (TMT)) and three physical tests (gait speed, grip strength, 5-time sit to stand)

RESULTS: Participants with high microvascular and macrovascular burden had worse cognitive (mean score difference = -0.30, 95\% confidence interval (CI) = -0.37 to -0.24) and physical (mean score difference = -0.32, 95\% CI = -0.38 to -0.26) function than those with low microvascular and macrovascular burden. Individuals with high microvascular burden alone had similarly lower scores than those with high macrovascular burden alone (cognitive function: -0.16, 95\% CI = -0.24 to -0.08 vs -0.13, 95\% CI = -0.20 to -0.06; physical function: -0.15, 95\% CI = -0.22 to -0.08 vs -0.12, 95\% CI = -0.18 to -0.06). Psychomotor speed and working memory, assessed using the TMT, were only impaired in the presence of high microvascular burden. Of the 11 vascular abnormalities considered, white matter hyperintensity, cystatin C-based glomerular filtration rate, large brain infarct, and ankle-arm index were independently associated with cognitive and physical function.

CONCLUSION: Microvascular and macrovascular abnormalities assessed using noninvasive tests of the brain, kidney, and peripheral artery were independently associated with poor cognitive and physical function in older adults. Future research should evaluate the usefulness of these tests in prognostication.

}, keywords = {Aged, Aged, 80 and over, Cognition, Cross-Sectional Studies, Female, Humans, Male, Neuropsychological Tests, Vascular Malformations}, issn = {1532-5415}, doi = {10.1111/jgs.13594}, author = {Kim, Dae Hyun and Grodstein, Francine and Newman, Anne B and Chaves, Paulo H M and Odden, Michelle C and Klein, Ronald and Sarnak, Mark J and Lipsitz, Lewis A} } @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 {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 {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 {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 {7337, title = {Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies.}, journal = {JAMA Cardiol}, volume = {2}, year = {2017}, month = {2017 Mar 01}, pages = {314-318}, abstract = {

Importance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.

Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.

Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.

Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation.

Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.

Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59\% (n = 8533) were women, and 44\% (n = 6363) were African American. Overall, 1461 (10\%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95\% CI, 19.3-24.8) and 6.2 (95\% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95\% CI, 21.6-27.5) and 8.4 (95\% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95\% CI, 11.3-15.5) and 4.8 (95\% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95\% CI, 1.2-3.3) for HF, 2.3 (95\% CI, 1.2-3.4) for CHD, and 0.8 (95\% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95\% CI, 1.5-5.5) and 7.8 (95\% CI, 2.2-13.3) per 1000 person-years, respectively.

Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2016.4652}, author = {Bansal, Nisha and Katz, Ronit and Robinson-Cohen, Cassianne and Odden, Michelle C and Dalrymple, Lorien and Shlipak, Michael G and Sarnak, Mark J and Siscovick, David S and Zelnick, Leila and Psaty, Bruce M and Kestenbaum, Bryan and Correa, Adolfo and Afkarian, Maryam and Young, Bessie and de Boer, Ian H} } @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 {7362, title = {Association of Blood Pressure Trajectory With Mortality, Incident Cardiovascular Disease, and Heart Failure in the Cardiovascular Health Study.}, journal = {Am J Hypertens}, year = {2017}, month = {2017 Mar 10}, abstract = {

BACKGROUND: Common blood pressure (BP) trajectories are not well established in elderly persons, and their association with clinical outcomes is uncertain.

METHODS: We used hierarchical cluster analysis to identify discrete BP trajectories among 4,067 participants in the Cardiovascular Health Study using repeated BP measures from years 0 to 7. We then evaluated associations of each BP trajectory cluster with all-cause mortality, incident cardiovascular disease (CVD, defined as stroke or myocardial infarction) (N = 2,837), and incident congestive heart failure (HF) (N = 3,633) using Cox proportional hazard models.

RESULTS: Median age was 77 years at year 7. Over a median 9.3 years of follow-up, there were 2,475 deaths, 659 CVD events, and 1,049 HF events. The cluster analysis identified 3 distinct trajectory groups. Participants in cluster 1 (N = 1,838) had increases in both systolic (SBP) and diastolic (DBP) BPs, whereas persons in cluster 2 (N = 1,109) had little change in SBP but declines in DBP. Persons in cluster 3 (N = 1,120) experienced declines in both SBP and DBP. After multivariable adjustment, clusters 2 and 3 were associated with increased mortality risk relative to cluster 1 (hazard ratio = 1.21, 95\% confidence interval: 1.06-1.37 and hazard ratio = 1.20, 95\% confidence interval: 1.05-1.36, respectively). Compared to cluster 1, cluster 3 had higher rates of incident CVD but associations were not statistically significant in demographic-adjusted models (hazard ratio = 1.16, 95\% confidence interval: 0.96-1.39). Findings were similar when stratified by use of antihypertensive therapy.

CONCLUSIONS: Among community-dwelling elders, distinct BP trajectories were identified by integrating both SBP and DBP. These clusters were found to have differential associations with outcomes.

}, issn = {1941-7225}, doi = {10.1093/ajh/hpx028}, author = {Smitson, Christopher C and Scherzer, Rebecca and Shlipak, Michael G and Psaty, Bruce M and Newman, Anne B and Sarnak, Mark J and Odden, Michelle C and Peralta, Carmen A} } @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 {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 {8572, title = {Visit-to-Visit Blood Pressure Variability and Mortality and Cardiovascular Outcomes Among Older Adults: The Health, Aging, and Body Composition Study.}, journal = {Am J Hypertens}, volume = {30}, year = {2017}, month = {2017 Feb}, pages = {151-158}, abstract = {

BACKGROUND: Level of blood pressure (BP) is strongly associated with cardiovascular (CV) events and mortality. However, it is questionable whether mean BP can fully capture BP-related vascular risk. Increasing attention has been given to the value of visit-to-visit BP variability.

METHODS: We examined the association of visit-to-visit BP variability with mortality, incident myocardial infarction (MI), and incident stroke among 1,877 well-functioning elders in the Health, Aging, and Body Composition Study. We defined visit-to-visit diastolic BP (DBP) and systolic BP (SBP) variability as the root-mean-square error of person-specific linear regression of BP as a function of time. Alternatively, we counted the number of considerable BP increases and decreases (separately; 10mm Hg for DBP and 20mm Hg for SBP) between consecutive visits for each individual.

RESULTS: Over an average follow-up of 8.5 years, 623 deaths (207 from CV disease), 153 MIs, and 156 strokes occurred. The median visit-to-visit DBP and SBP variability was 4.96 mmHg and 8.53 mmHg, respectively. After multivariable adjustment, visit-to-visit DBP variability was related to higher all-cause (hazard ratio (HR) = 1.18 per 1 SD, 95\% confidence interval (CI) = 1.01-1.37) and CV mortality (HR = 1.35, 95\% CI = 1.05-1.73). Additionally, individuals having more considerable decreases of DBP (>=10mm Hg between 2 consecutive visits) had higher risk of all-cause (HR = 1.13, 95\% CI = 0.99-1.28) and CV mortality (HR = 1.30, 95\% CI = 1.05-1.61); considerable increases of SBP (>=20mm Hg) were associated with higher risk of all-cause (HR = 1.18, 95\% CI = 1.03-1.36) and CV mortality (HR = 1.37, 95\% CI = 1.08-1.74).

CONCLUSIONS: Visit-to-visit DBP variability and considerable changes in DBP and SBP were risk factors for mortality in the elderly.

}, keywords = {Aged, Aging, Blood Pressure, Blood Pressure Determination, Body Composition, California, Cohort Studies, Female, Health Status, Humans, Hypertension, Incidence, Longitudinal Studies, Male, Myocardial Infarction, Office Visits, Prognosis, Retrospective Studies, Risk Factors, Stroke, Survival Rate}, issn = {1941-7225}, doi = {10.1093/ajh/hpw106}, author = {Wu, Chenkai and Shlipak, Michael G and Stawski, Robert S and Peralta, Carmen A and Psaty, Bruce M and Harris, Tamara B and Satterfield, Suzanne and Shiroma, Eric J and Newman, Anne B and Odden, Michelle C} } @article {7674, title = {Association of Frailty with Recovery from Disability among Community-Dwelling Older Adults: Results from Two Large U.S. Cohorts.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2018}, month = {2018 Apr 10}, abstract = {

Background: Disability in activities of daily living (ADLs) is a dynamic process and transitions among different disability states are common. However, little is known about factors affecting recovery from disability. We examined the association between frailty and recovery from disability among non-disabled community-dwelling elders.

Methods: We studied 1023 adults from the Cardiovascular Health Study (CHS) and 685 adults from the Health and Retirement Study (HRS), who were >=65 years and had incident disability, defined as having difficulty in >=1 ADL (dressing, eating, toileting, bathing, transferring, walking across a room). Disability recovery was defined as having no difficulty in any ADLs. Frailty was assessed by slowness, weakness, exhaustion, inactivity, and shrinking. Persons were classified as "non-frail" (0 criteria), "prefrail" (1-2 criteria), or "frail" (3-5 criteria).

Results: In total, 539 (52.7\%) CHS participants recovered from disability within one year. Almost two-thirds of non-frail persons recovered, while less than two-fifths of the frail recovered. In the HRS, 234 (34.2\%) participants recovered from disability within two years. Approximately half of the non-frail recovered, while less than one-fifth of the frail recovered. After adjustment, prefrail and frail CHS participants were 16\% and 36\% less likely to recover than the non-frail, respectively. In the HRS, frail persons had a 41\% lower likelihood of recovery than the non-frail.

Conclusions: Frailty is an independent predictor of poor recovery from disability among non-disabled older adults. These findings validate frailty as a marker of decreased resilience and may offer opportunities for individualized interventions and geriatric care based on frailty assessment.

}, issn = {1758-535X}, doi = {10.1093/gerona/gly080}, author = {Wu, Chenkai and Kim, Dae H and Xue, Qian-Li and Lee, David S H and Varadhan, Ravi and Odden, Michelle C} } @article {7662, title = {Development, Construct Validity, and Predictive Validity of a Continuous Frailty Scale: Results from Two Large U.S. Cohorts.}, journal = {Am J Epidemiol}, year = {2018}, month = {2018 Apr 24}, abstract = {

Frailty is an age-related clinical syndrome of decreased resilience to stressors. Among numerous assessments of frailty, the frailty phenotype (FP) scale, proposed by Fried and colleagues has been the most widely used one. We aimed to develop a continuous frailty scale that may overcome limitations facing the categorical FP scale and to evaluate its construct validity, predictive validity, and measurement properties. Data were from the Cardiovascular Health Study (N~=~4243) and Health and Retirement Study (N~=~7600). Frailty was conceptualized as a continuous construct, measured by five measures used in FP scale: gait speed, grip strength, exhaustion, physical activity, and weight loss. We used confirmatory factor analysis to investigate the relationship between five indicators and the latent frailty construct. We examined the association of the continuous frailty scale with mortality and disability. The unidimensional model fit the data satisfactorily; similar factor structure was observed across two cohorts. Gait speed and weight loss were the strongest and weakest indicators, respectively; grip strength, exhaustion, and physical activity had similar strength in measuring frailty. In each cohort, the continuous frailty scale was strongly associated with mortality and disability and persisted to be associated with outcomes among robust and prefrail persons classified by the FP scale.

}, issn = {1476-6256}, doi = {10.1093/aje/kwy041}, author = {Wu, Chenkai and Geldhof, G John and Xue, Qian-Li and Kim, Dae H and Newman, Anne B and Odden, Michelle C} } @article {7663, title = {Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study.}, journal = {Environ Int}, volume = {116}, year = {2018}, month = {2018 Apr 23}, pages = {239-247}, abstract = {

BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear.

OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY.

METHODS: We analyzed baseline (1989-1993) blood samples from 933 men >=65 years of age from the prospective Cardiovascular Health Study. Particulate matter <=10 μm (PM), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants{\textquoteright} monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR.

RESULTS: Increased PM was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (<=28.5 μg/m), the middle (28.5-31.0 μg/m; β = -0.0044, p = 0.09) and highest (>=31 μg/m; β = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (β = -0.00035, p = 0.06) and smoking pack-years (β = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants.

CONCLUSIONS: PM may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.

}, issn = {1873-6750}, doi = {10.1016/j.envint.2018.04.030}, author = {Wong, Jason Y Y and Margolis, Helene G and Machiela, Mitchell and Zhou, Weiyin and Odden, Michelle C and Psaty, Bruce M and Robbins, John and Jones, Rena R and Rotter, Jerome I and Chanock, Stephen J and Rothman, Nathaniel and Lan, Qing and Lee, Jennifer S} } @article {7918, title = {Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study.}, journal = {BMJ}, volume = {363}, year = {2018}, month = {2018 Oct 17}, pages = {k4067}, abstract = {

OBJECTIVE: To determine the longitudinal association between serial biomarker measures of circulating omega 3 polyunsaturated fatty acid (n3-PUFA) levels and healthy ageing.

DESIGN: Prospective cohort study.

SETTING: Four communities in the United States (Cardiovascular Health Study) from 1992 to 2015.

PARTICIPANTS: 2622 adults with a mean (SD) age of 74.4 (4.8) and with successful healthy ageing at baseline in 1992-93.

EXPOSURE: Cumulative levels of plasma phospholipid n3-PUFAs were measured using gas chromatography in 1992-93, 1998-99, and 2005-06, expressed as percentage of total fatty acids, including α-linolenic acid from plants and eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid from seafoood.

MAIN OUTCOME MEASURE: Healthy ageing defined as survival without chronic diseases (ie, cardiovascular disease, cancer, lung disease, and severe chronic kidney disease), the absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Events were centrally adjudicated or determined from medical records and diagnostic tests.

RESULTS: Higher levels of long chain n3-PUFAs were associated with an 18\% lower risk (95\% confidence interval 7\% to 28\%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15\% (6\% to 23\%) and 16\% (6\% to 25\%), respectively. α-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95\% confidence interval 0.83 to 1.02).

CONCLUSIONS: In older adults, a higher cumulative level of serially measured circulating n3-PUFAs from seafood (eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid), eicosapentaenoic acid, and docosapentaenoic acid (but not docosahexaenoic acid from seafood or α-linolenic acid from plants) was associated with a higher likelihood of healthy ageing. These findings support guidelines for increased dietary consumption of n3-PUFAs in older adults.

}, issn = {1756-1833}, doi = {10.1136/bmj.k4067}, author = {Lai, Heidi Tm and de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and McKnight, Barbara and Song, Xiaoling and King, Irena B and Chaves, Paulo Hm and Odden, Michelle C and Newman, Anne B and Siscovick, David S and Mozaffarian, Dariush} } @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 {8278, title = {Heterogeneous Exposure Associations in Observational Cohort Studies: The Example of Blood Pressure in Older Adults.}, journal = {Am J Epidemiol}, year = {2019}, month = {2019 Oct 08}, abstract = {

Heterogeneous exposure associations (HEAs) can be defined as differences in the association of a exposure with an outcome among subgroups that differ by a set of characteristics. This manuscript intends to foster discussion of HEAs in the epidemiological literature, and present a variant of the random forest algorithm that can be used to identify HEAs. We demonstrate the use of this algorithm in the setting of the association of systolic blood pressure and death in older adults. The training set included pooled data from the baseline examination of the Cardiovascular Health Study (1989-1993), the Health, Aging, and Body Composition study (1997-1998), and the Sacramento Area Latino Study on Aging (1998-1999). The test set included data from the National Health and Nutrition Examination Survey (1999-2002). The hazard ratios ranged from 1.25 (95\% CI: 1.13, 1.37) per 10 mmHg higher systolic blood pressure in men aged <=67 years with diastolic blood pressure >80 mmHg, to 1.00 (0.96, 1.03) in women with creatinine <0.7 mg/dL and a history of hypertension. HEAs have the potential to improve our understanding of disease mechanisms in diverse populations, and guide the design of randomized controlled trials to control exposures in heterogeneous populations.

}, issn = {1476-6256}, doi = {10.1093/aje/kwz218}, author = {Odden, Michelle C and Rawlings, Andreea M and Khodadadi, Abtin and Fern, Xiaoli and Shlipak, Michael G and Bibbins-Domingo, Kirsten and Covinsky, Kenneth and Kanaya, Alka M and Lee, Anne and Haan, Mary N and Newman, Anne B and Psaty, Bruce M and Peralta, Carmen A} } @article {8048, title = {The role of functional status on the relationship between blood pressure and cognitive decline: the Cardiovascular Health Study.}, journal = {J Hypertens}, year = {2019}, month = {2019 May 01}, abstract = {

OBJECTIVE: To examine whether self-reported functional status modified the association between blood pressure (BP) and cognitive decline among older adults.

METHODS: The study included 2097 US adults aged 75 years and older from the Cardiovascular Health Study, followed for up to 6 years. Functional status was ascertained by self-reported limitation in activities of daily living (ADL; none vs. any). Cognitive function was assessed by the Modified Mini Mental State Exam (3MSE). We used linear mixed models to examine whether the presence of at least one ADL limitation modified the association between BP and cognitive decline. Potential confounders included demographics, physiologic measures, antihypertensive medication use and apolipoprotein E ε4 allele. We conducted stratified analyses for significant interactions between BP and ADL.

RESULTS: The association between BP and change in 3MSE differed by baseline ADL limitation. Among participants without ADL limitation, elevated systolic BP (>=140 mmHg) was associated with a 0.15 decrease (95\% CI -0.24 to -0.07); P value for interaction less than 0.001, whereas in those with an ADL limitation, elevated systolic BP was independently associated with a 0.30 increase in 3MSE scores per year (95\% CI 0.06-0.55). Elevated diastolic BP (>=80 mmHg) was associated with an increase in cognitive function in both groups, although the increase was greater in those with ADL limitation (0.47 points per year vs. 0.18 points per year, P value for interaction = 0.01).

CONCLUSION: Elevated BP appears to be associated with a decrease in cognitive scores among functioning older adults, and modest improvements in cognitive function among poorly functioning elders.

}, issn = {1473-5598}, doi = {10.1097/HJH.0000000000002102}, author = {Miller, Lindsay M and Peralta, Carmen A and Fitzpatrick, Annette L and Wu, Chenkai and Psaty, Bruce M and Newman, Anne B and Odden, Michelle C} } @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 {8392, title = {Brachial Flow-mediated Dilation and Risk of Dementia: The Cardiovascular Health Study.}, journal = {Alzheimer Dis Assoc Disord}, volume = {34}, year = {2020}, month = {2020 Jul-Sep}, pages = {272-274}, abstract = {

INTRODUCTION: Brachial flow-mediated dilation (FMD) is a physiologic measure of endothelial function. We determined the prospective association of brachial FMD with incident dementia among older adults.

METHODS: We included 2777 Cardiovascular Health Study participants who underwent brachial FMD measurement. Incident dementia was ascertained by medication use, International Classification of Diseases-9 codes, requirement for a proxy, and death certificates and calibrated to gold-standard assessments performed in a subset of the cohort.

RESULTS: Mean participant age at time of brachial FMD measurement was 77.9 years. We identified 1650 incident dementia cases (median follow-up=10.5 y). After adjusting for age, race, sex, education, clinic site, and baseline arterial diameter, risk of dementia for participants in the highest quartile of percent brachial FMD did not differ from those in lowest quartile (hazard ratio=0.89, 95\% confidence interval: 0.77, 1.03).

CONCLUSIONS: Brachial FMD, measured late in life, is not associated with an increased risk of incident dementia.

}, issn = {1546-4156}, doi = {10.1097/WAD.0000000000000394}, author = {Garg, Parveen K and Tan, Annabel X and Odden, Michelle C and Gardin, Julius M and Lopez, Oscar L and Newman, Anne B and Rawlings, Andreea M and Mukamal, Kenneth J} } @article {8395, title = {Level and change in N-terminal pro B-type Natriuretic Peptide and kidney function and survival to age 90.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2020}, month = {2020 May 17}, abstract = {

BACKGROUND: Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years.

METHODS: The population included participants (n=3,645) in the Cardiovascular Health Study, aged between 67-75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study equation (BIS2), and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures.

RESULTS: There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 ml/min per 1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95\% CI: 1.13, 1.34) of survival to 90, and a 0.5 ml/min/ 1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95\% CI: 1.31, 1.74). A 2-fold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95\% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95\% CI: 0.43, 0.65) for survival to age 90.

CONCLUSION: eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.

}, issn = {1758-535X}, doi = {10.1093/gerona/glaa124}, author = {H{\"a}berle, Astrid D and Biggs, Mary L and Cushman, Mary and Psaty, Bruce M and Newman, Anne B and Shlipak, Michael G and Gottdiener, John and Wu, Chenkai and Gardin, Julius M and Bansal, Nisha 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 {8485, title = {Predicting Risk of Atherosclerotic Cardiovascular Disease Using Pooled Cohort Equations in Older Adults With Frailty, Multimorbidity, and Competing Risks.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Sep 15}, pages = {e016003}, abstract = {

Background Assessment of atherosclerotic cardiovascular disease (ASCVD) risk is crucial for prevention and management, but the performance of the pooled cohort equations in older adults with frailty and multimorbidity is unknown. We evaluated the pooled cohort equations in these subgroups and the impact of competing risks. Methods and Results In 4249 community-dwelling adults, aged >=65~years, from the CHS (Cardiovascular Health Study), we calculated 10-year risk of hard ASCVD. Frailty was determined using the Fried phenotype. Latent class analysis was used to identify individuals with multimorbidity patterns using chronic conditions. We assessed discrimination using the C-statistic and calibration by comparing predicted ASCVD risks with estimated risk using cause-specific and cumulative incidence models, by multimorbidity patterns and frailty status. A total of 917 (21.6\%) participants had an ASCVD event, and 706 (16.6\%) had a competing event of death. C-statistic was 0.68 in men and 0.69 in women; calibration was good when compared with cause-specific and cumulative incidence estimated risks (males, -0.1\% and 3.3\%; females, 0.6\% and 1.4\%). Latent class analysis identified 4 patterns: minimal disease, cardiometabolic, low cognition, musculoskeletal-lung depression. In the cardiometabolic pattern, ASCVD risk was overpredicted compared with cumulative incidence risk in men (7.4\%) and women (6.8\%). Risk was underpredicted in men (-10.7\%) and women (-8.2\%) with frailty compared with cause-specific risk. Miscalibration occurred mostly at high predicted risk ranges. Conclusions ASCVD prediction was good in this cohort of adults aged >=65~years. Although calibration varied by multimorbidity patterns, frailty, and competing risks, miscalibration was mostly present at high predicted risk ranges and thus less likely to alter decision making for primary prevention therapy.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.016003}, author = {Nguyen, Quoc Dinh and Odden, Michelle C and Peralta, Carmen A and Kim, Dae Hyun} } @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 {8790, title = {Association Between Myocardial Strain and Frailty in CHS.}, journal = {Circ Cardiovasc Imaging}, volume = {14}, year = {2021}, month = {2021 May}, pages = {e012116}, abstract = {

BACKGROUND: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association between myocardial strain and frailty-a clinical syndrome of lack of physiological reserve.

METHODS: Frailty was defined in participants of the CHS (Cardiovascular Health Study) as having >=3 of the following clinical criteria: weakness, slowness, weight loss, exhaustion, and inactivity. Using speckle-tracking echocardiography data, we examined the cross-sectional (n=3206) and longitudinal (n=1431) associations with frailty among participants who had at least 1 measure of myocardial strain, left ventricular longitudinal strain (LVLS), left ventricular early diastolic strain rate and left atrial reservoir strain, and no history of cardiovascular disease or heart failure at the time of echocardiography.

RESULTS: In cross-sectional analyses, lower (worse) LVLS was associated with prevalent frailty; this association was robust to adjustment for left ventricular ejection fraction (adjusted odds ratio, 1.32 [95\% CI, 1.07-1.61] per 1-SD lower strain; =0.007) and left ventricular stroke volume (adjusted OR, 1.32 [95\% CI, 1.08-1.61] per 1-SD lower strain; =0.007). In longitudinal analyses, adjusted associations of LVLS and left ventricular early diastolic strain with incident frailty were 1.35 ([95\% CI, 0.96-1.89] =0.086) and 1.58 ([95\% CI, 1.11-2.27] =0.013, respectively). Participants who were frail and had the worst LVLS had a 2.2-fold increased risk of death (hazard ratio, 2.20 [95\% CI, 1.81-2.66]; <0.0001).

CONCLUSIONS: In community-dwelling older adults without prevalent cardiovascular disease, worse LVLS by speckle-tracking echocardiography, reflective of subclinical myocardial dysfunction, was associated with frailty. Frailty and LVLS have an additive effect on mortality risk.

}, issn = {1942-0080}, doi = {10.1161/CIRCIMAGING.120.012116}, author = {Tan, Annabel X and Shah, Sanjiv J and Sanders, Jason L and Psaty, Bruce M and Wu, Chenkai and Gardin, Julius M and Peralta, Carmen A and Newman, Anne B 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 {8710, title = {Balance and cognitive decline in older adults in the cardiovascular health study.}, journal = {Age Ageing}, year = {2021}, month = {2021 Mar 10}, abstract = {

BACKGROUND: Previous studies have demonstrated an association between gait speed and cognitive function. However, the relationship between balance and cognition remains less well explored. This study examined the cross-sectional and longitudinal relationship of balance and cognitive decline in older adults.

METHODS: A cohort of 4,811 adults, aged >=65~years, participating in the Cardiovascular Health Study was followed for 6~years. Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST) were used to measure cognition. Tandem balance measures were used to evaluate balance. Regression models were adjusted for demographics, behavioural and disease factors.

RESULTS: Worse balance was independently associated with worse cognition in cross-sectional analysis. Longitudinally, participants aged >=76~years with poorer balance had a faster rate of decline after adjustment for co-variates: -0.97 points faster decline in 3MSE per year (95\% confidence interval (CI): -1.32, -0.63) compared to the participants with good balance. There was no association of balance and change in 3MSE among adults aged <76~years (P value for balance and age interaction < 0.0001). DSST scores reflected -0.21 (95\% CI: -0.37, -0.05) points greater decline when adjusted for co-variates. In Cox proportional hazard models, participants with worse balance had a higher risk of being cognitively impaired over the 6 years of follow-up visits (adjusted HR:1.72, 95\% CI: 1.30, 2.29).

CONCLUSIONS: Future studies should evaluate standing balance as a potential screening technique to identify individuals at risk of cognitive decline. Furthermore, a better understanding of the pathophysiological link between balance and cognition may inform strategies to prevent cognitive decline.

}, issn = {1468-2834}, doi = {10.1093/ageing/afab038}, author = {Meunier, Claire C and Smit, Ellen and Fitzpatrick, Annette L and Odden, Michelle C} } @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 {9159, title = {The association of hearing problems with social network strength and depressive symptoms: the cardiovascular health study.}, journal = {Age Ageing}, volume = {51}, year = {2022}, month = {2022 Aug 02}, abstract = {

BACKGROUND: research on the association between hearing impairment and psychosocial outcomes is not only limited but also yielded mixed results.

METHODS: we investigated associations between annual self-reports of hearing problems, depressive symptoms and social network strength among 5,888 adults from the Cardiovascular Health Study over a period of 9 years. Social network strength and depressive symptoms were defined using the Lubben Social Network Scale (LSNS), and the Center for Epidemiological Studies Depression Scale (CES-D).

RESULTS: hearing problems were associated with weaker social networks and more depressive symptoms. These association differed for prevalent versus incident hearing problems. Participants with prevalent hearing problems scored an adjusted 0.47 points lower (95\% CI: -2.20, -0.71) on the LSNS and 0.71 points higher (95\% CI: 0.23, 1.19) on the CES-D than those without hearing problems. Participants with incident hearing problems had a greater decline of 0.12 points (95\% CI: -0.12, -0.03) per year in social network score than individuals with no hearing problems after adjusting for confounders. Females appeared to be more vulnerable to changes in social network strength than males (P-value for interaction = 0.02), but not for changes in depressive score. Accounting for social network score did not appear to attenuate the association between hearing problems and depressive score.

CONCLUSION: findings suggest that older adults with prevalent hearing problems may be more at risk for depression, but individuals with incident hearing problems may be at greater risk for a winnowing of their social network.

}, keywords = {Aged, Depression, Female, Hearing Loss, Humans, Male, Self Report, Social Networking}, issn = {1468-2834}, doi = {10.1093/ageing/afac181}, author = {Dobrota, Sylvie D and Biggs, Mary L and Pratt, Sheila and Popat, Rita and Odden, Michelle C} } @article {9108, title = {Associations of modifiable behavioral risk factor combinations at 65-74 years old with cognitive healthspan over 20 years.}, journal = {Psychosom Med}, year = {2022}, month = {2022 Jun 28}, abstract = {

OBJECTIVE: Behavioral risk factors for dementia tend to co-occur and inter-relate, especially poor diet, physical inactivity, sleep disturbances, and depression. Having multiple of these modifiable behavioral risk factors (MBRFs) may predict a particularly shortened cognitive healthspan, and therefore, may signal high-risk status/high intervention need.

METHODS: This secondary analyses of data from the Cardiovascular Health Study included 3149 participants aged 65-74 years (mean age = 69.5, standard deviation (SD) = 2.5; 59.6\% female). MBRF exposures were self-reports regarding: (1) diet, (2) activity, (3) sleep, and (4) depression symptoms. We primarily analyzed MBRF counts. Over up to 26 years of follow-up, we assessed the: (1) number of remaining cognitively healthy life years (CHLYs); and (2) percentage of remaining life years (LYs) that were CHLYs (\%CHLY). We estimated CHLYs as time before a dementia diagnosis, cognitive screener scores indicating impairment, proxy port indicating significant cognitive decline, or dementia medication use.

RESULTS: Participants averaged a remaining 16 LYs (SD = 7), 12.2 CHLYs (SD = 6.6), and 78.1\% of LYs being CHLYs (SD = 25.6). Compared with having no MBRFs, having one was associated with ~1 less LY and CHLY, but not a relatively lower \%CHLY. In contrast, having 3+ MBRFs was associated with about 2-3 fewer LYs and CHLYs as well as about 6\% lower \%CHLY (95\% confidence interval: -9.0, -2.5 \%CHLYs), p = 0.001).

CONCLUSIONS: MBRF-related reductions in the cognitive healthspan are most apparent when people have multiple MBRFs. Future research is needed to determine if/how behavioral risks converge mechanistically, and if dementia prevention efficacy improves when targeting MBRF combinations.

}, issn = {1534-7796}, doi = {10.1097/PSY.0000000000001100}, author = {Smagula, Stephen F and Biggs, Mary L and Jacob, Mini E and Rawlings, Andreea M and Odden, Michelle C and Arnold, Alice and Newman, Anne B and Buysse, Daniel J} } @article {9255, title = {Plasma proteomic signature of decline in gait speed and grip strength.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Dec}, pages = {e13736}, abstract = {

The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60\% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55\% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p~< 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p~= 1.58 {\texttimes} 10 ), pleiotrophin (1.23 {\texttimes} 10 ), and TIMP-1 (5.97 {\texttimes} 10 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 {\texttimes} 10 ), CDON (2.38 {\texttimes} 10 ), and SMOC1 (7.47 {\texttimes} 10 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.

}, keywords = {Adult, Female, Gait, Hand Strength, Humans, Independent Living, Male, Proteomics, Walking Speed}, issn = {1474-9726}, doi = {10.1111/acel.13736}, author = {Liu, Xiaojuan and Pan, Stephanie and Xanthakis, Vanessa and Vasan, Ramachandran S and Psaty, Bruce M and Austin, Thomas R and Newman, Anne B and Sanders, Jason L and Wu, Chenkai and Tracy, Russell P and Gerszten, Robert E and Odden, Michelle C} } @article {9086, title = {Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.}, journal = {Eur J Epidemiol}, year = {2022}, month = {2022 Jul 05}, abstract = {

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61\% women, mean age 74~years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

}, issn = {1573-7284}, doi = {10.1007/s10654-022-00888-z}, author = {Austin, Thomas R and McHugh, Caitlin P and Brody, Jennifer A and Bis, Joshua C and Sitlani, Colleen M and Bartz, Traci M and Biggs, Mary L and Bansal, Nisha and B{\r u}zkov{\'a}, Petra and Carr, Steven A and deFilippi, Christopher R and Elkind, Mitchell S V and Fink, Howard A and Floyd, James S and Fohner, Alison E and Gerszten, Robert E and Heckbert, Susan R and Katz, Daniel H and Kizer, Jorge R and Lemaitre, Rozenn N and Longstreth, W T and McKnight, Barbara and Mei, Hao and Mukamal, Kenneth J and Newman, Anne B and Ngo, Debby and Odden, Michelle C and Vasan, Ramachandran S and Shojaie, Ali and Simon, Noah and Smith, George Davey and Davies, Neil M and Siscovick, David S and Sotoodehnia, Nona and Tracy, Russell P and Wiggins, Kerri L and Zheng, Jie and Psaty, Bruce M} } @article {9483, title = {Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.}, journal = {Aging Cell}, year = {2023}, month = {2023 Sep 11}, abstract = {

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 {\texttimes} 10 ) among 3838 older adults aged >=65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17\%) and 82 (46\%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p = 1 {\texttimes} 10 , p = 2 {\texttimes} 10 ), transgelin (TAGLN; p = 2 {\texttimes} 10 , p = 6 {\texttimes} 10 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p = 5 {\texttimes} 10 , p = 1 {\texttimes} 10 ) and with a lower level of growth hormone receptor (GHR, p = 3 {\texttimes} 10 , p = 2 {\texttimes} 10 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 {\texttimes} 10 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

}, issn = {1474-9726}, doi = {10.1111/acel.13975}, author = {Liu, Fangyu and Austin, Thomas R and Schrack, Jennifer A and Chen, Jingsha and Walston, Jeremy and Mathias, Rasika A and Grams, Morgan and Odden, Michelle C and Newman, Anne and Psaty, Bruce M and Ramonfaur, Diego and Shah, Amil M and Windham, B Gwen and Coresh, Josef and Walker, Keenan A} }