@article {678, title = {Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia.}, journal = {Am J Cardiol}, volume = {89}, year = {2002}, month = {2002 Feb 15}, pages = {419-24}, abstract = {

Depression is associated with increased cardiovascular disease, but the underlying mechanisms are not well understood. This study examines associations of depressive symptoms with inflammation and coagulation factors in persons aged > 65 years. Blood samples were obtained from 4,268 subjects free of cardiovascular disease (age 72.4 +/- 5.5 years, 2,623 women). Inflammation markers were C-reactive protein (CRP), white blood cell (WBC) count, total platelet count, and albumin; coagulation factors included factors VIIc and VIIIc and fibrinogen. Depression was assessed with the Center for Epidemiologic Studies Depression scale, and states of energy depletion with a validated exhaustion index. Statistical adjustments were made for risk factors (age, sex, race, systolic blood pressure, smoking status, diabetes mellitus) and physical measures of frailty (isometric handgrip, timed 15-feet walk test, activity level). Depression was associated with elevated CRP (3.31 +/- 0.10 vs 3.51 +/- 0.21 mg/L), WBC (6.14 +/- 0.03 vs 6.43 +/- 0.11 10(6)/L), fibrinogen (319 +/- 1 vs 326 +/- 3 mg/dl), and factor VIIc (124.6 +/- 0.6\% vs 127.2 +/- 1.3\%; all p <0.05). Exhaustion also was related to elevated inflammation and coagulation markers (p < 0.05). Exhausted men had markedly elevated CRP levels (6.82 +/- 2.10 mg/L) versus nonexhausted men (3.05 +/- 0.16: p = 0.007). After adjustment for control variables, exhaustion remained associated with albumin (p = 0.033), fibrinogen (p = 0.017), CRP (p = 0.066), and WBC (p = 0.060), whereas associations of depressive symptoms with biochemistry measures lost statistical significance. Thus, depression and exhaustion are associated with low-grade inflammation and elevated coagulation factors in persons aged > 65 years.

}, keywords = {Aged, Blood Chemical Analysis, Blood Coagulation Factors, Cardiovascular Diseases, Depression, Female, Humans, Inflammation, Male, Risk Factors}, issn = {0002-9149}, doi = {10.1016/s0002-9149(01)02264-0}, author = {Kop, Willem J and Gottdiener, John S and Tangen, Catherine M and Fried, Linda P and McBurnie, Mary Ann and Walston, Jeremy and Newman, Anne and Hirsch, Calvin and Tracy, Russell P} } @article {757, title = {"Successful aging": effect of subclinical cardiovascular disease.}, journal = {Arch Intern Med}, volume = {163}, year = {2003}, month = {2003 Oct 27}, pages = {2315-22}, abstract = {

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

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

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

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

}, keywords = {Aged, Aged, 80 and over, Aging, C-Reactive Protein, Cardiovascular Diseases, Female, Health Status, Humans, Longitudinal Studies, Male, Quality of Life, Regression Analysis, Risk Factors}, issn = {0003-9926}, doi = {10.1001/archinte.163.19.2315}, author = {Newman, Anne B and Arnold, Alice M and Naydeck, Barbara L and Fried, Linda P and Burke, Gregory L and Enright, Paul and Gottdiener, John and Hirsch, Calvin and O{\textquoteright}Leary, Daniel and Tracy, Russell} } @article {732, title = {Transitions in spousal caregiving.}, journal = {Gerontologist}, volume = {43}, year = {2003}, month = {2003 Apr}, pages = {230-41}, abstract = {

PURPOSE: This study describes transitions over 5 years among community-dwelling elderly spouses into and within caregiving roles and associated health outcomes.

DESIGN AND METHODS: Participants in the Caregiver Health Effects Study (n = 818) were interviewed four times over 5 years with changes in their caregiving status described. Analyses of the effect on health outcomes of transitions were performed on those for whom four observations were available (n = 428).

RESULTS: Only half (49.5\%) of noncaregivers at baseline remained noncaregivers at 5-year follow-up. The remainder experienced one or more transitions, including moving into the caregiving role, their own or their spouse{\textquoteright}s death, or placement of their spouse in a long-term care facility. The trajectory of health outcomes associated with caregiving was generally downward. Those who transitioned to heavy caregiving had more symptoms of depression, and poorer self-reported health and health behaviors.

IMPLICATIONS: Transitions into and within the caregiving role should be monitored for adverse health effects on the caregiver, with interventions tailored to the individual{\textquoteright}s location in the caregiving trajectory.

}, keywords = {Adaptation, Psychological, Aged, Aged, 80 and over, Caregivers, Female, Health Behavior, Health Status, Humans, Long-Term Care, Male, Residence Characteristics, Spouses, Stress, Psychological, Time Factors}, issn = {0016-9013}, doi = {10.1093/geront/43.2.230}, author = {Burton, Lynda C and Zdaniuk, Bozena and Schulz, Richard and Jackson, Sharon and Hirsch, Calvin} } @article {814, title = {Associates of bone mineral density in older African Americans.}, journal = {J Natl Med Assoc}, volume = {96}, year = {2004}, month = {2004 Dec}, pages = {1609-15}, abstract = {

OBJECTIVES: To assess correlates of bone mineral density (BMD) in older African Americans.

PARTICIPANTS: 189 women and 115 men over age 64.

METHODS: Variables investigated: BMD by dual X-ray absorptiometry (DXA), medications, cardiovascular disease risk factors, demographic, lifestyle factors and functional status. Variables showing univariate correlation with BMD (p < or = 0.1) were entered into sex-stratified linear regression models.

RESULTS: Age range 67-96 (mean 75). The mean BMD (gm/ cm2 +/- standard deviation) is reported for three sites. Total body: 1.03 (+/- 0.12) in women, 1.21 (+/- 0.11) in men. Spine: 1.05 (+/- 0.24) in women, 1.22 (+/- 0.26) in men. Total hip: 0.85 (+/- 0.15) in women, 1.04 (+/- 0.17) in men. Gender was significantly associated with BMD (t-test, p < 0.001). The R2 for tested variables were highly significant only for weight. Age was only significant for total hip in women (p < 0.05). Each kilogram of weight change was associated with a 5.3-6.8 mg/cm2 change in BMD.

CONCLUSIONS: In a population-based cohort of older African Americans, average BMD was significantly greater in men than women. Weight accounted for most of the explained variability (R2) in BMD; age added little to the overall R2. Lower-weight, older African-American men and women are at significantly increased risk for low BMD and, thus, likely to be at greater risk for osteoporotic fracture.

}, keywords = {Aged, Body Weight, Bone Density, Cross-Sectional Studies, Female, Humans, Male, Osteoporosis, Risk Factors}, issn = {0027-9684}, author = {Robbins, John and Hirsch, Calvin and Cauley, Jane} } @article {865, title = {Kidney function as a predictor of noncardiovascular mortality.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3728-35}, abstract = {

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95\% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Cohort Studies, Confidence Intervals, Creatinine, Cystatin C, Cystatins, Female, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Kidney Function Tests, Longitudinal Studies, Male, Probability, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Survival Analysis, United States}, issn = {1046-6673}, doi = {10.1681/ASN.2005040384}, author = {Fried, Linda F and Katz, Ronit and Sarnak, Mark J and Shlipak, Michael G and Chaves, Paulo H M and Jenny, Nancy Swords and Stehman-Breen, Catherine and Gillen, Dan and Bleyer, Anthony J and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {864, title = {A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {165}, year = {2005}, month = {2005 Oct 24}, pages = {2214-20}, abstract = {

BACKGROUND: Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear.

METHODS: Baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women 65 years or older, enrolled in 1989-1990 or 1992-1993 in 4 US communities.

RESULTS: A total of 1205 participants were in the lowest hemoglobin quintile (<13.7 g/dL for men; <12.6 g/dL for women), and 498 (8.5\%) were anemic (<13 g/dL for men; <12 g/dL for women). A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95\% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95\% CI, 1.25-1.62) and 1.24 (95\% CI, 1.09-1.42). After multivariate adjustment, these hazard ratios were 1.33 (95\% CI, 1.15-1.54) and 1.17 (95\% CI, 1.01-1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95\% CI, 1.38-1.78) and 1.38 (95\% CI, 1.19-1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations.

CONCLUSIONS: Lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The World Health Organization criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly and on the increased mortality at the extremes of hemoglobin concentrations.

}, keywords = {Age Factors, Aged, Anemia, California, Female, Follow-Up Studies, Health Status, Hemoglobins, Humans, Male, Maryland, Multivariate Analysis, North Carolina, Observation, Pennsylvania, Prospective Studies, Risk Factors, Severity of Illness Index, Survival Rate}, issn = {0003-9926}, doi = {10.1001/archinte.165.19.2214}, author = {Zakai, Neil A and Katz, Ronit and Hirsch, Calvin and Shlipak, Michael G and Chaves, Paulo H M and Newman, Anne B and Cushman, Mary} } @article {877, title = {The association of race with frailty: the cardiovascular health study.}, journal = {Ann Epidemiol}, volume = {16}, year = {2006}, month = {2006 Jul}, pages = {545-53}, abstract = {

PURPOSE: Frailty, which has been conceptualized as a state of decreased physiologic reserve contributing to functional decline, has a prevalence among older African Americans that is twice that in older whites. This study assesses the independent contribution of race to frailty.

METHODS: We evaluated 786 African-American and 4491 white participants of the Cardiovascular Health Study (CHS). Frailty is defined as meeting three or more of five criteria derived from CHS measures: lowest quintile for grip strength, self-reported exhaustion, unintentional weight loss of 10 lbs or greater in 1 year, slowest quintile for gait speed, and lowest quintile for physical activity. Controlling for age, sex, comorbidity, socioeconomic factors, and race, multinomial logistic regression estimated the odds ratio (OR) of prefrail (one or two criteria) to not frail and frail to not frail.

RESULTS: Among African Americans, 8.7\% of men and 15.0\% of women were frail compared with 4.6\% and 6.8\% of white men and women, respectively. In adjusted models, nonobese African Americans had a fourfold greater odds of frailty compared with whites. The increased OR of frailty associated with African-American race was less pronounced among those who were obese or disabled.

CONCLUSION: African-American race is associated independently with frailty.

}, keywords = {African Americans, Aged, Asthenia, Cardiovascular Diseases, Cohort Studies, Cross-Sectional Studies, European Continental Ancestry Group, Female, Frail Elderly, Health Status, Humans, Male, Middle Aged, Motor Activity, Odds Ratio, United States, Weight Loss}, issn = {1047-2797}, doi = {10.1016/j.annepidem.2005.10.003}, author = {Hirsch, Calvin and Anderson, Melissa L and Newman, Anne and Kop, Willem and Jackson, Sharon and Gottdiener, John and Tracy, Russell and Fried, Linda P} } @article {1201, title = {Health benefits of increased walking for sedentary, generally healthy older adults: using longitudinal data to approximate an intervention trial.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Sep}, pages = {982-9}, abstract = {

BACKGROUND: Older adults are often advised to walk more, but randomized trials have not conclusively established the benefits of walking in this age group. Typical analyses based on observational data may have biased results. Here, we propose a "limited-bias," more interpretable estimate of the health benefits to sedentary healthy older adults of walking more, using longitudinal data from the Cardiovascular Health Study.

METHODS: The number of city blocks walked per week, collected annually, was classified as sedentary (<7 blocks per week), somewhat active, or active (>or=28). Analysis was restricted to persons sedentary and healthy in the first 2 years. In Year 3, some became more active (the treatment groups). Self-rated health at Year 5 (follow-up) was regressed on walking at Year 3, with additional covariates from Year 2, when all were sedentary.

RESULTS: At follow-up, 83.5\% of those active at baseline had excellent, very good, or good self-rated health, as compared with 63.9\% of the sedentary, an apparent benefit of 19.6 percentage points. After covariate adjustment, the limited-bias estimate of the benefit was 11.2 percentage points (95\% confidence interval 3.7-18.6). Ten different outcome measures showed a benefit, ranging from 5 to 11 percentage points. Estimates from other study designs were smaller, less interpretable, and potentially more biased.

CONCLUSIONS: In longitudinal studies where walking and health are ascertained at every wave, limited-bias estimates can provide better estimates of the benefits of walking. A surprisingly small increase in walking was associated with meaningful health benefits.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Data Interpretation, Statistical, Female, Health Status, Health Surveys, Humans, Longitudinal Studies, Male, Regression Analysis, Sedentary Lifestyle, Walking}, issn = {1758-535X}, doi = {10.1093/gerona/glq070}, author = {Diehr, Paula and Hirsch, Calvin} } @article {1404, title = {Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 Nov}, pages = {3944-50}, abstract = {

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

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

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

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

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

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

}, keywords = {Aged, 80 and over, Female, Humans, Longitudinal Studies, Male, Thyroid Diseases, Thyroid Function Tests, Thyroid Gland, Thyrotropin, Thyroxine, Triiodothyronine}, issn = {1945-7197}, doi = {10.1210/jc.2012-2481}, author = {Waring, Avantika C and Arnold, Alice M and Newman, Anne B and B{\r u}zkov{\'a}, Petra and Hirsch, Calvin and Cappola, Anne R} } @article {5992, title = {Decline in health for older adults: five-year change in 13 key measures of standardized health.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {68}, year = {2013}, month = {2013 Sep}, pages = {1059-67}, abstract = {

BACKGROUND: The health of older adults declines over time, but there are many ways of measuring health. It is unclear whether all health measures decline at the same rate or whether some aspects of health are less sensitive to aging than others.

METHODS: We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, activities of daily living, instrumental activities of daily living, and gait speed. Each measure was standardized against self-rated health. We compared the 5-year change to see which of the 13 measures declined the fastest and the slowest.

RESULTS: The 5-year change in standardized health varied from a decline of 12 points (out of 100) for hospitalization to a decline of 17 points for gait speed. In most comparisons, standardized health from hospitalization and bed days declined the least, whereas health measured by activities of daily living, instrumental activities of daily living, and gait speed declined the most. These rankings were independent of age, sex, mortality patterns, and the method of standardization.

CONCLUSIONS: All of the health variables declined, on average, with advancing age, but at significantly different rates. Standardized measures of mental health, cognition, quality of life, and hospital utilization did not decline as fast as gait speed, activities of daily living, and instrumental activities of daily living. Public health interventions to address problems with gait speed, activities of daily living, and instrumental activities of daily living may help older adults to remain healthier in all dimensions.

}, keywords = {Activities of Daily Living, Aged, Aging, Cohort Studies, Female, Gait, Health Status, Health Status Indicators, Hospitalization, Humans, Longitudinal Studies, Male, Mental Health, Quality of Life, Self Report, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt038}, author = {Diehr, Paula H and Thielke, Stephen M and Newman, Anne B and Hirsch, Calvin and Tracy, Russell} } @article {6243, title = {Serum carboxymethyl-lysine, disability, and frailty in older persons: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Jun}, pages = {710-6}, abstract = {

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

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

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

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

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Aging, Biomarkers, Cardiac Rehabilitation, Cardiovascular Diseases, Disabled Persons, Female, Follow-Up Studies, Frail Elderly, Health Status, Humans, Incidence, Lysine, Male, Prevalence, Prognosis, Retrospective Studies, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glt155}, author = {Whitson, Heather E and Arnold, Alice M and Yee, Laura M and Mukamal, Kenneth J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Siscovick, David and Tracy, Russell P and Thielke, Stephen M and Hirsch, Calvin and Newman, Anne B and Zieman, Susan} } @article {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 {6659, title = {Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Mar 6}, pages = {363-71}, abstract = {

BACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study.

RESULTS: The development cohort included 828 participants who had a mean age of 80 ({\textpm}5.6) years and an eGFR of 47 ({\textpm}11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 ({\textpm}2.8) years and an eGFR of 50 ({\textpm}9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95\% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8\% among participants with the lowest scores to 83.6\% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95\% confidence interval, 0.64 to 0.74).

CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Albuminuria, Continental Population Groups, Creatinine, Diabetes Mellitus, Female, Glomerular Filtration Rate, Heart Failure, Humans, Male, Proportional Hazards Models, Regression Analysis, Renal Insufficiency, Chronic, Risk Factors, Sex Factors, Smoking, Stroke}, issn = {1555-905X}, doi = {10.2215/CJN.04650514}, author = {Bansal, Nisha and Katz, Ronit and de Boer, Ian H and Peralta, Carmen A and Fried, Linda F and Siscovick, David S and Rifkin, Dena E and Hirsch, Calvin and Cummings, Steven R and Harris, Tamara B and Kritchevsky, Stephen B and Sarnak, Mark J and Shlipak, Michael G and Ix, Joachim H} } @article {7247, title = {Can a Healthy Lifestyle Compress the Disabled Period in Older Adults?}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Oct}, pages = {1952-1961}, abstract = {

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

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

SETTING: Four U.S. communities.

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

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

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

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

}, issn = {1532-5415}, doi = {10.1111/jgs.14314}, author = {Jacob, Mini E and Yee, Laura M and Diehr, Paula H and Arnold, Alice M and Thielke, Stephen M and Chaves, Paulo H M and Gobbo, Liana Del and Hirsch, Calvin and Siscovick, David and Newman, Anne B} } @article {7592, title = {Soluble Inflammatory Markers and Risk of Incident Fractures in Older Adults: The Cardiovascular Health Study.}, journal = {J Bone Miner Res}, year = {2017}, month = {2017 Oct 04}, abstract = {

Several in vitro and animal studies have showed that inflammatory markers play a role in bone remodeling and pathogenesis of osteoporosis. Additionally, some human longitudinal studies showed suggestive associations between elevated inflammatory markers and increased risk of nontraumatic fractures. We examined several inflammatory markers and multiple fracture types in a single study of older individuals with extensive follow-up. We assessed the association of four inflammatory markers with the risk of incident hip fractures among 5265 participants of the Cardiovascular Health Study (CHS) and a composite endpoint of incident fractures of the hip, pelvis, humerus, or proximal forearm in 4477 participants. Among CHS participants followed between 1992 and 2009, we observed 480 incident hip fractures during a median follow-up of 11 years. In the composite fracture analysis cohort of 4477 participants, we observed 711 fractures during a median follow-up of 7 years. Adjusted hazard ratios (HRs) and 95\% confidence intervals (CIs) for hip fracture associated with doubling of IL-6 were HR 1.15 (95\% CI, 1.02 to 1.30) overall and HR 1.17 (95\% CI, 1.01 to 1.35) in women. We also observed a positive association between each unit increase in white blood cell (WBC) count and risk of hip fracture: HR 1.04 (95\% CI, 1.01 to 1.06) overall and HR 1.06 (95\% CI, 0.95 to 1.20) in women. We observed no significant associations between any of the four inflammatory markers and a composite fracture endpoint. Our findings suggest that chronic inflammatory and immune processes may be related to higher rates of incident hip fractures. {\textcopyright} 2017 American Society for Bone and Mineral Research.

}, issn = {1523-4681}, doi = {10.1002/jbmr.3301}, author = {Stojanovi{\'c}, Danijela and B{\r u}zkov{\'a}, Petra and Mukamal, Kenneth J and Heckbert, Susan R and Psaty, Bruce M and Fink, Howard A and Cauley, Jane A and Wallace, Erin and Curtis, Lesley H and Hirsch, Calvin and Budoff, Matthew and Li, Dong and Young, Rebekah and Jalal, Diana and Delaney, Joseph Ac} } @article {8045, title = {Advanced glycation end product carboxymethyl-lysine and risk of incident peripheral artery disease in older adults: The Cardiovascular Health Study.}, journal = {Diab Vasc Dis Res}, year = {2019}, month = {2019 May 08}, pages = {1479164119847481}, abstract = {

Carboxymethyl-lysine is an advanced glycation end product that is detectable in the serum. Higher carboxymethyl-lysine levels have been associated with increased risk of coronary heart disease, stroke and cardiovascular mortality. We determined whether high carboxymethyl-lysine levels are also associated with the risk of peripheral artery disease in Cardiovascular Health Study participants who were all aged 65 years and older at baseline. Multivariate Cox proportional hazards models were used to determine the association of baseline carboxymethyl-lysine levels with incident peripheral artery disease in 3267 individuals followed for a median length of 10.0 years. A total of 157 cases of incident peripheral artery disease occurred during follow-up. No significant relationship between carboxymethyl-lysine and risk of peripheral artery disease was found (hazard ratio per standard deviation increment = 1.03; 95\% confidence interval = 0.87, 1.23).

}, issn = {1752-8984}, doi = {10.1177/1479164119847481}, author = {Garg, Parveen K and Biggs, Mary L and Barzilay, Joshua and Djouss{\'e}, Luc and Hirsch, Calvin and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Newman, Anne B and Siscovick, David S and Mukamal, Kenneth J} } @article {8499, title = {Pre-diabetes, diabetes and predictors of incident angina among older women and men in the Cardiovascular Health Study.}, journal = {Diab Vasc Dis Res}, volume = {17}, year = {2020}, month = {2020 Jan-Feb}, pages = {1479164119888476}, abstract = {

Diabetes mellitus and angina pectoris are important conditions in older persons. The utility of pre-diabetes mellitus, diabetes mellitus and other risk factors as predictors of incident angina pectoris among older adults has not been characterized. We examined incident angina pectoris rates by sex and diabetes mellitus status in 4511 adults aged ⩾65 years without coronary heart disease at baseline from the Cardiovascular Health Study. Cox regression examined predictors of incident angina pectoris, including pre-diabetes mellitus or diabetes mellitus adjusted for sociodemographic characteristics and other risk factors, over 12.2 {\textpm} 6.9 years of follow-up. Overall, 39.1\% of participants had pre-diabetes mellitus, 14.0\% had diabetes mellitus and 532 (11.8\%) had incident angina pectoris. Incident angina pectoris rates per 1000 person-years in those with neither condition, pre-diabetes mellitus, and diabetes mellitus were 7.9, 9.0 and 12.3 in women and 10.3, 11.2 and 14.5 in men, respectively. Pre-diabetes mellitus and diabetes mellitus were not independently associated with incident AP; however, key predictors of AP were male sex, low-density lipoprotein-cholesterol, triglycerides, systolic blood pressure, antihypertensive medication and difficulty performing at least one instrumental activity of daily living (all < 0.05 to < 0.01). In our cohort of older adult participants, while the incidence of AP is greater in those with diabetes mellitus, neither diabetes mellitus nor pre-diabetes mellitus independently predicted incident angina pectoris.

}, keywords = {Age Factors, Aged, Angina Pectoris, Diabetes Mellitus, Female, Humans, Incidence, Male, Prediabetic State, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Sex Factors, Time Factors, United States}, issn = {1752-8984}, doi = {10.1177/1479164119888476}, author = {Mathenge, Njambi and Fan, Wenjun and Wong, Nathan D and Hirsch, Calvin and Delaney, Chris Joseph and Amsterdam, Ezra A and Koch, Bruce and Calara, Rico and Gardin, Julius M} } @article {8840, title = {Statins and cognitive decline in the Cardiovascular Health Study: A comparison of different analytical approaches.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2021}, month = {2021 Jul 31}, abstract = {

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

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

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

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

}, issn = {1758-535X}, doi = {10.1093/gerona/glab220}, author = {Zeki Al Hazzouri, Adina and Jawadekar, Neal and Grasset, Leslie and Kaiser, Paulina and Kezios, Katrina and Calonico, Sebastian and Glymour, M Maria and Hirsch, Calvin and Arnold, Alice M and Varadhan, Ravi and Opoodden, Michelle C} } @article {9257, title = {Fasting and Post-Load Glucose and Non-Esterified Fatty Acids and Risk of Heart Failure and its Subtypes in Older Adults.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2022}, month = {2022 Nov 14}, abstract = {

BACKGROUND: Glucose and non-esterified fatty acids (NEFA) are myocardial fuels whose fasting and post-prandial levels are under different homeostatic regulation. The relationships of fasting and post-load glucose and NEFA with incident heart failure (HF) remain incompletely defined.

METHODS: Serum glucose and NEFA were measured during fasting and 2 hours post oral glucose tolerance test, performed in Cardiovascular Health Study participants not receiving hypoglycemic medication. Participants with prevalent HF or lacking relevant data were excluded. Outcomes were incident HF (primary), and HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (secondary).

RESULTS: Among 2238 participants (age 78{\textpm}4) with median follow-up of 9.9 years, there were 737 HF events. After adjustment for demographic and lifestyle factors, both fasting (HR=1.11 per SD [95\% CI=1.01-1.23], p=0.040) and post-load (HR=1.14 per SD [1.05-1.24], p=0.002) glucose were significantly associated with incident HF. No association was seen for fasting or post-load NEFA. Upon mutual adjustment, only post-load glucose (HR=1.11 [1.003-1.22], p=0.044), but not fasting glucose (HR=1.06 [0.94-1.20], p=0.340), remained associated with HF. Further adjustment for cardiovascular disease and other risk factors in the causal pathway did not affect the association for post-load glucose, but eliminated that for fasting glucose. Associations for fasting and post-load glucose appeared stronger with higher adiposity, and were observed specifically for HFrEF, but not HFpEF.

CONCLUSIONS: Fasting and post-load glucose, but not NEFA, were associated with incident HF. The association was especially robust for post-load glucose, suggesting that pathways involved in post-prandial dysglycemia could offer new targets for HF prevention late in life.

}, issn = {1758-535X}, doi = {10.1093/gerona/glac229}, author = {Oesterle, Adam and B{\r u}zkov{\'a}, Petra and Pellegrini, Cara and Hirsch, Calvin and Tracy, Russell P and Siscovick, David S and Djouss{\'e}, Luc and Mukamal, Ken J and Kizer, Jorge R} } @article {9485, title = {Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Sep 05}, pages = {e029960}, abstract = {

Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50\% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95\% CI, 1.0-1.9]; =0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95\% CI, 1.0-1.3]; =0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95\% CI, 1.1-2.7]; =0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Heart Failure, Humans, Incidence, Ketone Bodies}, issn = {2047-9980}, doi = {10.1161/JAHA.123.029960}, author = {Niezen, Sebastian and Connelly, Margery A and Hirsch, Calvin and Kizer, Jorge R and Benitez, Maria E and Minchenberg, Scott and Perez-Matos, Maria Camila and Jiang, Zhenghui Gordon and Mukamal, Kenneth J} } @article {9317, title = {Social networks, social support, and life expectancy in older adults: the Cardiovascular Health Study.}, journal = {Arch Gerontol Geriatr}, volume = {111}, year = {2023}, month = {2023 Mar 03}, pages = {104981}, abstract = {

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

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

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

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

}, issn = {1872-6976}, doi = {10.1016/j.archger.2023.104981}, author = {Bhatia, Roma and Hirsch, Calvin and Arnold, Alice M and Newman, Anne B and Mukamal, Kenneth J} }