@article {1038, title = {Adiponectin and risk of coronary heart disease in older men and women.}, journal = {J Clin Endocrinol Metab}, volume = {93}, year = {2008}, month = {2008 Sep}, pages = {3357-64}, abstract = {

CONTEXT: Despite established insulin-sensitizing and antiatherogenic preclinical effects, epidemiological investigations of adiponectin have yielded conflicting findings, and its relationship with coronary heart disease (CHD) remains uncertain.

OBJECTIVE: Our objective was to investigate the relationship between adiponectin and CHD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: This was a case-control study (n = 1386) nested within the population-based Cardiovascular Health Study from 1992--2001. Controls were frequency-matched to cases by age, sex, race, subclinical cardiovascular disease, and center.

MAIN OUTCOME MEASURES: Incident CHD was defined as angina pectoris, percutaneous or surgical revascularization, nonfatal myocardial infarction (MI), or CHD death. A more restrictive CHD endpoint was limited to nonfatal MI and CHD death.

RESULTS: Adiponectin exhibited significant negative correlations with baseline adiposity, insulin resistance, dyslipidemia, inflammatory markers, and leptin. After controlling for matching factors, adjustment for waist to hip ratio, hypertension, smoking, alcohol, low-density lipoprotein cholesterol, creatinine, and leptin revealed a modestly increased risk of incident CHD with adiponectin concentrations at the upper end [odds ratio = 1.37 (quintile 5 vs. 1-4), 95\% confidence interval 1.02-1.84]. This association was stronger when the outcome was limited to nonfatal MI and fatal CHD (odds ratio = 1.69, 95\% confidence interval 1.23-2.32). The findings were not influenced by additional adjustment for weight change, health status, or cystatin C, nor were they abolished by adjustment for potential mediators.

CONCLUSIONS: This study shows an association between adiponectin and increased risk of first-ever CHD in older adults. Further research is needed to elucidate the basis for the concurrent beneficial and detrimental aspects of this relationship, and under what circumstances one or the other may predominate.

}, keywords = {Adiponectin, Age Factors, Aged, Aged, 80 and over, Body Weight, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Humans, Longitudinal Studies, Male, Odds Ratio, Risk Factors}, issn = {0021-972X}, doi = {10.1210/jc.2008-0640}, author = {Kizer, Jorge R and Barzilay, Joshua I and Kuller, Lewis H and Gottdiener, John S} } @article {1214, title = {Change in circulating adiponectin in advanced old age: determinants and impact on physical function and mortality. The Cardiovascular Health Study All Stars Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {65}, year = {2010}, month = {2010 Nov}, pages = {1208-14}, abstract = {

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

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

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

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

}, keywords = {Adiponectin, Age Factors, Aged, Aging, Analysis of Variance, Cardiovascular Diseases, Cause of Death, Chi-Square Distribution, Cohort Studies, Cross-Sectional Studies, Female, Health Status, Humans, Linear Models, Male, Physical Fitness, Proportional Hazards Models, Risk Factors, Sex Factors, Time Factors, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glq122}, author = {Kizer, Jorge R and Arnold, Alice M and Strotmeyer, Elsa S and Ives, Diane G and Cushman, Mary and Ding, Jingzhong and Kritchevsky, Stephen B and Chaves, Paulo H M and Hirsch, Calvin H and Newman, Anne B} } @article {1292, title = {Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study.}, journal = {J Am Coll Cardiol}, volume = {57}, year = {2011}, month = {2011 May 24}, pages = {2172-80}, abstract = {

OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts.

BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke.

METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995).

RESULTS: The mean age of the participants was 74.5 {\textpm} 4.8 years, and 39.3\% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95\% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings.

CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

}, keywords = {Aged, Aortic Valve Stenosis, Brain, Brain Infarction, Calcinosis, Cohort Studies, Female, Humans, Magnetic Resonance Imaging, Male, Mitral Valve Stenosis, Retrospective Studies}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.01.034}, author = {Rodriguez, Carlos J and Bartz, Traci M and Longstreth, W T and Kizer, Jorge R and Barasch, Eddy and Lloyd-Jones, Donald M and Gottdiener, John S} } @article {1326, title = {Association of body mass index with peripheral arterial disease in older adults: the Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {174}, year = {2011}, month = {2011 Nov 01}, pages = {1036-43}, abstract = {

The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)(2)) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged >= 65 years at baseline (1989-1990 or 1992-1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14\%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95\% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95\% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95\% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95\% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.

}, keywords = {Aged, Ankle Brachial Index, Body Mass Index, Cross-Sectional Studies, Health Status, Humans, Kaplan-Meier Estimate, Longitudinal Studies, Male, Obesity, Peripheral Arterial Disease, Prevalence, Sex Factors, Smoking, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwr228}, author = {Ix, Joachim H and Biggs, Mary L and Kizer, Jorge R and Mukamal, Kenneth J and Djouss{\'e}, Luc and Zieman, Susan J and de Boer, Ian H and Nelson, Tracy L and Newman, Anne B and Criqui, Michael H and Siscovick, David S} } @article {1339, title = {Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults.}, journal = {Stroke}, volume = {42}, year = {2011}, month = {2011 Dec}, pages = {3347-51}, abstract = {

BACKGROUND AND PURPOSE: Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in nondiabetic, older adults.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and from fasting and 2-hour postload insulin and glucose; a lower Gutt index indicates higher insulin resistance.

RESULTS: Analyses included 3442 participants (42\% men) with a mean age of 73 years. Incidence of ischemic stroke was 9.8 strokes per 1000 person-years. The relative risk (RR) for lowest quartile versus highest quartile of Gutt index was 1.64 (95\% CI, 1.24-2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile versus lowest quartile of 2-hour glucose was 1.84 (95\% CI, 1.39-2.42). In contrast, the adjusted RR for highest quartile versus lowest quartile of fasting insulin was 1.10 (95\% CI, 0.84-1.46).

CONCLUSIONS: In nondiabetic, older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not by fasting insulin, was associated with risk of incident ischemic stroke.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Brain Ischemia, Fasting, Female, Humans, Incidence, Insulin Resistance, Male, Risk, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.111.620773}, author = {Thacker, Evan L and Psaty, Bruce M and McKnight, Barbara and Heckbert, Susan R and Longstreth, W T and Mukamal, Kenneth J and Meigs, James B and de Boer, Ian H and Boyko, Edward J and Carnethon, Mercedes R and Kizer, Jorge R and Tracy, Russell P and Smith, Nicholas L and Siscovick, David S} } @article {1296, title = {Longitudinal changes in adiponectin and inflammatory markers and relation to survival in the oldest old: the Cardiovascular Health Study All Stars study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Oct}, pages = {1100-7}, abstract = {

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

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

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

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

}, keywords = {Adiponectin, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Chi-Square Distribution, Enzyme-Linked Immunosorbent Assay, Female, Humans, Inflammation, Interleukin-6, Male, Mortality, Predictive Value of Tests, Risk Factors, Sensitivity and Specificity, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glr098}, author = {Kizer, Jorge R and Arnold, Alice M and Jenny, Nancy S and Cushman, Mary and Strotmeyer, Elsa S and Ives, Diane G and Ding, Jingzhong and Kritchevsky, Stephen B and Chaves, Paulo H M and Hirsch, Calvin H and Newman, Anne B} } @article {1254, title = {Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women.}, journal = {Am J Epidemiol}, volume = {173}, year = {2011}, month = {2011 Jan 01}, pages = {10-25}, abstract = {

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (>= 30 kg/m{\texttwosuperior}) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m{\texttwosuperior} was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95\% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95\% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

}, keywords = {Adiposity, Age Factors, Aged, Aged, 80 and over, Brain Ischemia, Coronary Disease, Female, Humans, Incidence, Male, Middle Aged, Obesity, Prevalence, Retrospective Studies, Risk Factors, Sex Factors, United States}, issn = {1476-6256}, doi = {10.1093/aje/kwq311}, author = {Kizer, Jorge R and Biggs, Mary L and Ix, Joachim H and Mukamal, Kenneth J and Zieman, Susan J and de Boer, Ian H and Mozaffarian, Dariush and Barzilay, Joshua I and Strotmeyer, Elsa S and Luchsinger, Jos{\'e} A and Elkind, Mitchell S V and Longstreth, W T and Kuller, Lewis H and Siscovick, David S} } @article {1563, title = {Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies.}, journal = {Lancet}, volume = {377}, year = {2011}, month = {2011 Mar 26}, pages = {1085-95}, abstract = {

BACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease.

METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios.

RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95\% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19\%, -0.05\%, and -0.05\%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95\% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70).

INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.

FUNDING: British Heart Foundation and UK Medical Research Council.

}, keywords = {Age Factors, Blood Pressure, Body Mass Index, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Diabetes Mellitus, Female, Humans, Male, Middle Aged, Obesity, Abdominal, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Factors, Smoking, Systole, Waist Circumference, Waist-Hip Ratio}, issn = {1474-547X}, doi = {10.1016/S0140-6736(11)60105-0}, author = {Wormser, David and Kaptoge, Stephen and Di Angelantonio, Emanuele and Wood, Angela M and Pennells, Lisa and Thompson, Alex and Sarwar, Nadeem and Kizer, Jorge R and Lawlor, Debbie A and Nordestgaard, B{\o}rge G and Ridker, Paul and Salomaa, Veikko and Stevens, June and Woodward, Mark and Sattar, Naveed and Collins, Rory and Thompson, Simon G and Whitlock, Gary and Danesh, John} } @article {1344, title = {Adiposity and incident heart failure in older adults: the cardiovascular health study.}, journal = {Obesity (Silver Spring)}, volume = {20}, year = {2012}, month = {2012 Sep}, pages = {1936-41}, abstract = {

While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident HF in older adults. We sought to examine the association between waist circumference (WC) and incident HF and assess whether sex modifies the relation between WC and HF. Prospective study using data on 4,861 participants of the Cardiovascular Health Study (1989-2007). HF was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio (HR). The mean age was 73.0 years for men and 72.3 years for women; 42.5\% were men and 15.3\% were African Americans. WC was positively associated with an increased risk of HF: each standard deviation of WC was associated with a 14\% increased risk of HF (95\% CI: 3\%-26\%) in a multivariable model. There was not a statistically significant sex-by-WC interaction (P = 0.081). BMI was positively associated with incident HF (HR: 1.22 (95\% CI: 1.15-1.29) per standard deviation increase of BMI); however, this association was attenuated and became nonstatistically significant upon additional adjustment for WC (HR: 1.09 (95\% CI: 0.99-1.21)). In conclusion, a higher WC is associated with an increased risk of HF independent of BMI in community-living older men and women.

}, keywords = {Adiposity, Aged, Aging, Body Fat Distribution, Body Mass Index, Female, Heart Failure, Humans, Incidence, Independent Living, Male, Obesity, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, United States, Waist Circumference}, issn = {1930-739X}, doi = {10.1038/oby.2011.320}, author = {Djouss{\'e}, Luc and Bartz, Traci M and Ix, Joachim H and Zieman, Susan J and Delaney, Joseph A and Mukamal, Kenneth J and Gottdiener, John S and Siscovick, David S and Kizer, Jorge R} } @article {1380, title = {Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study.}, journal = {Circulation}, volume = {125}, year = {2012}, month = {2012 May 15}, pages = {2316-22}, abstract = {

BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD).

METHODS AND RESULTS: Among 3710 community-living individuals >= 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 {\textpm} 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00-1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01).

CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those >= 75 years of age.

}, keywords = {African Continental Ancestry Group, Age Distribution, Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Body Mass Index, C-Reactive Protein, Cardiovascular Diseases, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Humans, Incidence, Life Style, Lipids, Male, Pilot Projects, Prevalence, Proportional Hazards Models, Residence Characteristics, Risk Factors, Sex Distribution}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.111.072751}, author = {Ix, Joachim H and Biggs, Mary L and Mukamal, Kenneth J and Kizer, Jorge R and Zieman, Susan J and Siscovick, David S and Mozzaffarian, Dariush and Jensen, Majken K and Nelson, Lauren and Ruderman, Neil and Djouss{\'e}, Luc} } @article {1553, title = {Associations of total and high-molecular-weight adiponectin with all-cause and cardiovascular mortality in older persons: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {126}, year = {2012}, month = {2012 Dec 18}, pages = {2951-61}, abstract = {

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

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

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

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Female, Health Surveys, Humans, Male, Molecular Weight}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.112.135202}, author = {Kizer, Jorge R and Benkeser, David and Arnold, Alice M and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Tracy, Russell P and Mantzoros, Christos S and deFilippi, Christopher R and Newman, Anne B and Djouss{\'e}, Luc} } @article {5860, title = {Hemoglobin A1c and arterial and ventricular stiffness in older adults.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e47941}, abstract = {

OBJECTIVE: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA(1c), an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.

RESEARCH DESIGN \& METHODS: Baseline HbA(1c) was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged >= 65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA(1c) and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.

RESULTS: HbA(1c) was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA(1c) was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.

CONCLUSIONS: In this sample of older adults without diabetes, HbA(1c) was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.

}, keywords = {Adult, African Continental Ancestry Group, Aged, Ankle Brachial Index, Arteries, Blood Glucose, Blood Pressure, Body Mass Index, Cross-Sectional Studies, Fasting, Female, Genetic Association Studies, Glycated Hemoglobin A, Glycation End Products, Advanced, Heart Ventricles, Humans, Male, Middle Aged, Ultrasonography, Vascular Stiffness}, issn = {1932-6203}, doi = {10.1371/journal.pone.0047941}, author = {Zieman, Susan J and Kamineni, Aruna and Ix, Joachim H and Barzilay, Joshua and Djouss{\'e}, Luc and Kizer, Jorge R and Biggs, Mary L and de Boer, Ian H and Chonchol, Michel and Gottdiener, John S and Selvin, Elizabeth and Newman, Anne B and Kuller, Lewis H and Siscovick, David S and Mukamal, Kenneth J} } @article {1407, title = {The impact of height on the risk of atrial fibrillation: the Cardiovascular Health Study.}, journal = {Eur Heart J}, volume = {33}, year = {2012}, month = {2012 Nov}, pages = {2709-17}, abstract = {

AIMS: Atrial fibrillation (AF) is the most common sustained arrhythmia. Increased body size has been associated with AF, but the relationship is not well understood. In this study, we examined the effect of increased height on the risk of AF and explore potential mediators and implications for clinical practice.

METHODS AND RESULTS: We examined data from 5860 individuals taking part in the Cardiovascular Health Study, a cohort study of older US adults followed for a median of 13.6 (women) and 10.3 years (men). Multivariate linear models and age-stratified Cox proportional hazards and risk models were used, with focus on the effect of height on both prevalent and incident AF. Among 684 (22.6\%) and 568 (27.1\%) incident cases in women and men, respectively, greater height was significantly associated with AF risk [hazard ratio (HR)(women) per 10 cm 1.32, confidence interval (CI) 1.16-1.50, P < 0.0001; HR(men) per 10 cm 1.26, CI 1.11-1.44, P < 0.0001]. The association was such that the incremental risk from sex was completely attenuated by the inclusion of height (for men, HR 1.48, CI 1.32-1.65, without height, and HR 0.94, CI 0.85-1.20, with height included). Inclusion of height in the Framingham model for incident AF improved discrimination. In sequential models, however, we found minimal attenuation of the risk estimates for AF with adjustment for left ventricular (LV) mass and left atrial (LA) dimension. The associations of LA and LV size measurements with AF risk were weakened when indexed to height.

CONCLUSION: Independent from sex, increased height is significantly associated with the risk of AF.

}, keywords = {Aged, Atrial Fibrillation, Body Height, Epidemiologic Methods, Female, Humans, Male, Sex Factors, United States}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehs301}, author = {Rosenberg, Michael A and Patton, Kristen K and Sotoodehnia, Nona and Karas, Maria G and Kizer, Jorge R and Zimetbaum, Peter J and Chang, James D and Siscovick, David and Gottdiener, John S and Kronmal, Richard A and Heckbert, Susan R and Mukamal, Kenneth J} } @article {1361, title = {Nonesterified fatty acids and risk of sudden cardiac death in older adults.}, journal = {Circ Arrhythm Electrophysiol}, volume = {5}, year = {2012}, month = {2012 Apr}, pages = {273-8}, abstract = {

BACKGROUND: Although nonesterified fatty acids (NEFA) have been positively associated with coronary heart disease risk factors, limited and inconsistent data are available on the relation between NEFA and sudden cardiac death.

METHODS AND RESULTS: Using a prospective design, we studied 4657 older men and women (mean age, 75 years) from the Cardiovascular Health Study (1992-2006) to evaluate the association between plasma NEFA and the risk of sudden cardiac death in older adults. Plasma concentrations of NEFA were measured using established enzymatic methods, and sudden death was adjudicated using medical records, death certificates, proxy interview, and autopsy reports. We used Cox proportional hazard models to estimate multivariable-adjusted relative risks. During a median follow-up of 10.0 years, 221 new cases of sudden cardiac death occurred. In a multivariable model adjusting for age, sex, race, clinic site, alcohol intake, smoking, prevalent coronary heart disease and heart failure, and self-reported health status, relative risks (95\% confidence interval) for sudden cardiac death were 1.0 (ref), 1.15 (0.81-1.64), 1.06 (0.72-1.55), and 0.91 (0.60-1.38) across consecutive quartiles of NEFA concentration. In secondary analyses restricted to the first 5 years of follow-up, we also did not observe a statistically significant association between plasma NEFA and sudden cardiac death.

CONCLUSIONS: Our data do not provide evidence for an association between plasma NEFA measured late in life and the risk of sudden cardiac death in older adults.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Death, Sudden, Cardiac, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Retrospective Studies, Risk Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.111.967661}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Ix, Joachim H and Kizer, Jorge R and Lemaitre, Rozenn N and Sotoodehnia, Nona and Zieman, Susan J and Mozaffarian, Dariush and Tracy, Russell P and Mukamal, Kenneth J and Siscovick, David S} } @article {1378, title = {Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002607}, abstract = {

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5{\texttimes}10(-8)-1.2{\texttimes}10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3{\texttimes}10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3{\texttimes}10(-3), n = 22,044), increased triglycerides (p = 2.6{\texttimes}10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8{\texttimes}10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4{\texttimes}10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5{\texttimes}10(-13), n = 96,748) and decreased BMI (p = 1.4{\texttimes}10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

}, keywords = {Adiponectin, African Americans, Asian Continental Ancestry Group, Cholesterol, HDL, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002607}, author = {Dastani, Zari and Hivert, Marie-France and Timpson, Nicholas and Perry, John R B and Yuan, Xin and Scott, Robert A and Henneman, Peter and Heid, Iris M and Kizer, Jorge R and Lyytik{\"a}inen, Leo-Pekka and Fuchsberger, Christian and Tanaka, Toshiko and Morris, Andrew P and Small, Kerrin and Isaacs, Aaron and Beekman, Marian and Coassin, Stefan and Lohman, Kurt and Qi, Lu and Kanoni, Stavroula and Pankow, James S and Uh, Hae-Won and Wu, Ying and Bidulescu, Aurelian and Rasmussen-Torvik, Laura J and Greenwood, Celia M T and Ladouceur, Martin and Grimsby, Jonna and Manning, Alisa K and Liu, Ching-Ti and Kooner, Jaspal and Mooser, Vincent E and Vollenweider, Peter and Kapur, Karen A and Chambers, John and Wareham, Nicholas J and Langenberg, Claudia and Frants, Rune and Willems-Vandijk, Ko and Oostra, Ben A and Willems, Sara M and Lamina, Claudia and Winkler, Thomas W and Psaty, Bruce M and Tracy, Russell P and Brody, Jennifer and Chen, Ida and Viikari, Jorma and K{\"a}h{\"o}nen, Mika and Pramstaller, Peter P and Evans, David M and St Pourcain, Beate and Sattar, Naveed and Wood, Andrew R and Bandinelli, Stefania and Carlson, Olga D and Egan, Josephine M and B{\"o}hringer, Stefan and van Heemst, Diana and Kedenko, Lyudmyla and Kristiansson, Kati and Nuotio, Marja-Liisa and Loo, Britt-Marie and Harris, Tamara and Garcia, Melissa and Kanaya, Alka and Haun, Margot and Klopp, Norman and Wichmann, H-Erich and Deloukas, Panos and Katsareli, Efi and Couper, David J and Duncan, Bruce B and Kloppenburg, Margreet and Adair, Linda S and Borja, Judith B and Wilson, James G and Musani, Solomon and Guo, Xiuqing and Johnson, Toby and Semple, Robert and Teslovich, Tanya M and Allison, Matthew A and Redline, Susan and Buxbaum, Sarah G and Mohlke, Karen L and Meulenbelt, Ingrid and Ballantyne, Christie M and Dedoussis, George V and Hu, Frank B and Liu, Yongmei and Paulweber, Bernhard and Spector, Timothy D and Slagboom, P Eline and Ferrucci, Luigi and Jula, Antti and Perola, Markus and Raitakari, Olli and Florez, Jose C and Salomaa, Veikko and Eriksson, Johan G and Frayling, Timothy M and Hicks, Andrew A and Lehtim{\"a}ki, Terho and Smith, George Davey and Siscovick, David S and Kronenberg, Florian and van Duijn, Cornelia and Loos, Ruth J F and Waterworth, Dawn M and Meigs, James B and Dupuis, Jos{\'e}e and Richards, J Brent and Voight, Benjamin F and Scott, Laura J and Steinthorsdottir, Valgerdur and Dina, Christian and Welch, Ryan P and Zeggini, Eleftheria and Huth, Cornelia and Aulchenko, Yurii S and Thorleifsson, Gudmar and McCulloch, Laura J and Ferreira, Teresa and Grallert, Harald and Amin, Najaf and Wu, Guanming and Willer, Cristen J and Raychaudhuri, Soumya and McCarroll, Steve A and Hofmann, Oliver M and Segr{\`e}, Ayellet V and van Hoek, Mandy and Navarro, Pau and Ardlie, Kristin and Balkau, Beverley and Benediktsson, Rafn and Bennett, Amanda J and Blagieva, Roza and Boerwinkle, Eric and Bonnycastle, Lori L and Bostr{\"o}m, Kristina Bengtsson and Bravenboer, Bert and Bumpstead, Suzannah and Burtt, Noel P and Charpentier, Guillaume and Chines, Peter S and Cornelis, Marilyn and Crawford, Gabe and Doney, Alex S F and Elliott, Katherine S and Elliott, Amanda L and Erdos, Michael R and Fox, Caroline S and Franklin, Christopher S and Ganser, Martha and Gieger, Christian and Grarup, Niels and Green, Todd and Griffin, Simon and Groves, Christopher J and Guiducci, Candace and Hadjadj, Samy and Hassanali, Neelam and Herder, Christian and Isomaa, Bo and Jackson, Anne U and Johnson, Paul R V and J{\o}rgensen, Torben and Kao, Wen H L and Kong, Augustine and Kraft, Peter and Kuusisto, Johanna and Lauritzen, Torsten and Li, Man and Lieverse, Aloysius and Lindgren, Cecilia M and Lyssenko, Valeriya and Marre, Michel and Meitinger, Thomas and Midthjell, Kristian and Morken, Mario A and Narisu, Narisu and Nilsson, Peter and Owen, Katharine R and Payne, Felicity and Petersen, Ann-Kristin and Platou, Carl and Proen{\c c}a, Christine and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, N William and Robertson, Neil R and Rocheleau, Ghislain and Roden, Michael and Sampson, Michael J and Saxena, Richa and Shields, Beverley M and Shrader, Peter and Sigurdsson, Gunnar and Spars{\o}, Thomas and Strassburger, Klaus and Stringham, Heather M and Sun, Qi and Swift, Amy J and Thorand, Barbara and Tichet, Jean and Tuomi, Tiinamaija and van Dam, Rob M and van Haeften, Timon W and van Herpt, Thijs and van Vliet-Ostaptchouk, Jana V and Walters, G Bragi and Weedon, Michael N and Wijmenga, Cisca and Witteman, Jacqueline and Bergman, Richard N and Cauchi, Stephane and Collins, Francis S and Gloyn, Anna L and Gyllensten, Ulf and Hansen, Torben and Hide, Winston A and Hitman, Graham A and Hofman, Albert and Hunter, David J and Hveem, Kristian and Laakso, Markku and Morris, Andrew D and Palmer, Colin N A and Rudan, Igor and Sijbrands, Eric and Stein, Lincoln D and Tuomilehto, Jaakko and Uitterlinden, Andre and Walker, Mark and Watanabe, Richard M and Abecasis, Goncalo R and Boehm, Bernhard O and Campbell, Harry and Daly, Mark J and Hattersley, Andrew T and Pedersen, Oluf and Barroso, In{\^e}s and Groop, Leif and Sladek, Rob and Thorsteinsdottir, Unnur and Wilson, James F and Illig, Thomas and Froguel, Philippe and van Duijn, Cornelia M and Stefansson, Kari and Altshuler, David and Boehnke, Michael and McCarthy, Mark I and Soranzo, Nicole and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and M{\"a}gi, Reedik and Randall, Joshua and Elliott, Paul and Rybin, Denis and Dehghan, Abbas and Hottenga, Jouke Jan and Song, Kijoung and Goel, Anuj and Lajunen, Taina and Doney, Alex and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Timpson, Nicholas J and Zabena, Carina and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ariyurek, Yavuz and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Bergmann, Sven and Bochud, Murielle and Bonnefond, Am{\'e}lie and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Grundy, Scott and Gwilliam, Rhian and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Hillman, David R and Hingorani, Aroon D and Hui, Jennie and Hung, Joe and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Mahley, Robert and Mangino, Massimo and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Mukherjee, Sutapa and Naitza, Silvia and Neville, Matthew J and Orr{\`u}, Marco and Pakyz, Ruth and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigur{\dh}sson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and T{\"o}njes, Anke and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Ward, Kim L and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Silander, Kaisa and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Serrano-R{\'\i}os, Manuel and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pramstaller, Peter Paul and Wright, Alan F and Stumvoll, Michael and Hamsten, Anders and Buchanan, Thomas A and Valle, Timo T and Rotter, Jerome I and Penninx, Brenda W J H and Boomsma, Dorret I and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Peltonen, Leena and Mooser, Vincent and Sladek, Robert and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Chasman, Daniel I and Johansen, Christopher T and Fouchier, Sigrid W and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Feitosa, Mary F and Orho-Melander, Marju and Melander, Olle and Li, Xiaohui and Li, Mingyao and Cho, Yoon Shin and Go, Min Jin and Kim, Young Jin and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Ong, Rick Twee-Hee and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Whitfield, John B and Thompson, John R and Surakka, Ida and Spector, Tim D and Smit, Johannes H and Sinisalo, Juha and Scott, James and Saharinen, Juha and Sabatti, Chiara and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Parker, Alex N and Par{\'e}, Guillaume and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Lucas, Gavin and Luben, Robert and Lokki, Marja-Liisa and Lettre, Guillaume and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaplan, Lee M and Johansson, Asa and Janssens, A Cecile J W and Igl, Wilmar and Hovingh, G Kees and Hengstenberg, Christian and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Groop, Leif C and Gonzalez, Elena and Freimer, Nelson B and Erdmann, Jeanette and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Faire, Ulf and Crawford, Gabriel and Chen, Yii-der I and Caulfield, Mark J and Boekholdt, S Matthijs and Assimes, Themistocles L and Quertermous, Thomas and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Taylor, Herman A and Gabriel, Stacey B and Holm, Hilma and Gudnason, Vilmundur and Krauss, Ronald M and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Strachan, David P and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and Kathiresan, Sekar} } @article {1386, title = {Plasma fatty acid-binding protein 4, nonesterified fatty acids, and incident diabetes in older adults.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Aug}, pages = {1701-7}, abstract = {

OBJECTIVE: To examine the relation of fatty acid-binding protein (FABP)4 and nonesterified fatty acids (NEFAs) to diabetes in older adults.

RESEARCH DESIGN AND METHODS: We ascertained incident diabetes among 3,740 Cardiovascular Health Study participants (1992-2007) based on the use of hypoglycemic medications, fasting glucose >= 126 mg/dL, or nonfasting glucose >= 200 mg/dL. FABP4 and NEFA were measured on specimens collected between 1992 and 1993.

RESULTS: Mean age of the 3,740 subjects studied was 74.8 years. For each SD increase in log FABP4, hazard ratios (HRs) for diabetes were 1.35 (95\% CI 1.10-1.65) for women and 1.45 (1.13-1.85) for men controlling for age, race, education, physical activity, cystatin C, alcohol intake, smoking, self-reported health status, and estrogen use for women (P for sex-FABP4 interaction 0.10). BMI modified the FABP4-diabetes relation (P = 0.009 overall; 0.02 for women and 0.135 for men), in that statistically significant higher risk of diabetes was mainly seen in men with BMI <25 kg/m(2) (HR per SD: 1.78 [95\% CI 1.13-2.81]). There was a modest and nonsignificant association of NEFA with diabetes (P(trend) = 0.21). However, when restricted to the first 5 years of follow-up, multivariable-adjusted HRs for diabetes were 1.0 (ref.), 1.68 (95\% CI 1.12-2.53), and 1.63 (1.07-2.50) across consecutive tertiles of NEFA (P(trend) = 0.03).

CONCLUSIONS: Plasma FABP4 was positively associated with incident diabetes in older adults, and such association was statistically significant in lean men only. A significant positive association between plasma NEFA and incident diabetes was observed during the first 5 years of follow-up.

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Diabetes Mellitus, Fatty Acid-Binding Proteins, Fatty Acids, Nonesterified, Female, Humans, Male, Prospective Studies}, issn = {1935-5548}, doi = {10.2337/dc11-1690}, author = {Djouss{\'e}, Luc and Khawaja, Owais and Bartz, Traci M and Biggs, Mary L and Ix, Joachim H and Zieman, Susan J and Kizer, Jorge R and Tracy, Russell P and Siscovick, David S and Mukamal, Kenneth J} } @article {1379, title = {Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {110}, year = {2012}, month = {2012 Jul 15}, pages = {212-6}, abstract = {

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women >=65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 {\textpm} 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95\% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.

}, keywords = {Aged, Atrial Fibrillation, C-Reactive Protein, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Hypertension, Incidence, Lipoproteins, HDL, Lipoproteins, LDL, Male, Natriuretic Peptide, Brain, Obesity, Peptide Fragments, Prospective Studies, Sex Factors, Triglycerides, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2012.03.010}, author = {Khawaja, Owais and Bartz, Traci M and Ix, Joachim H and Heckbert, Susan R and Kizer, Jorge R and Zieman, Susan J and Mukamal, Kenneth J and Tracy, Russell P and Siscovick, David S and Djouss{\'e}, Luc} } @article {1356, title = {Total and high-molecular-weight adiponectin and risk of incident diabetes in older people.}, journal = {Diabetes Care}, volume = {35}, year = {2012}, month = {2012 Feb}, pages = {415-23}, abstract = {

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

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

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

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

}, keywords = {Adiponectin, Aged, Diabetes Mellitus, Female, Humans, Male, Risk Factors}, issn = {1935-5548}, doi = {10.2337/dc11-1519}, author = {Kizer, Jorge R and Arnold, Alice M and Benkeser, David and Ix, Joachim H and Djouss{\'e}, Luc and Zieman, Susan J and Barzilay, Joshua I and Tracy, Russell P and Mantzoros, Christos S and Siscovick, David S and Mukamal, Kenneth J} } @article {5849, title = {Adiposity and cognitive decline in the cardiovascular health study.}, journal = {Neuroepidemiology}, volume = {40}, year = {2013}, month = {2013}, pages = {274-81}, abstract = {

BACKGROUND: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study.

METHODS: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline.

RESULTS: The final sample was comprised of 2,681 women (57.9\%) and 1,949 men (42.1\%) aged 73 {\textpm} 5.2 and 73.9 {\textpm} 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease.

CONCLUSIONS: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions.

}, keywords = {Adiposity, Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cognition Disorders, Electric Impedance, Female, Humans, Male, Risk Factors, Waist Circumference, Waist-Hip Ratio}, issn = {1423-0208}, doi = {10.1159/000345136}, author = {Luchsinger, Jos{\'e} A and Biggs, Mary L and Kizer, Jorge R and Barzilay, Joshua and Fitzpatrick, Annette and Newman, Anne and Longstreth, William T and Lopez, Oscar and Siscovick, David and Kuller, Lewis} } @article {6062, title = {Circulating 25-hydroxyvitamin D is associated with insulin resistance cross-sectionally but not longitudinally in older adults: The Cardiovascular Health Study.}, journal = {Metabolism}, volume = {62}, year = {2013}, month = {2013 Dec}, pages = {1788-94}, abstract = {

BACKGROUND: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear.

OBJECTIVE: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults.

METHODS AND RESULTS: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95\% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA-IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-β, in either cross-sectional or longitudinal analysis.

CONCLUSIONS: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors.

}, keywords = {Adiposity, Aged, Anthropometry, Cardiovascular Diseases, Cross-Sectional Studies, Exercise, Female, Humans, Hydroxycholecalciferols, Inflammation, Insulin, Insulin Resistance, Longitudinal Studies, Male, Middle Aged, Obesity, Risk Factors, Surveys and Questionnaires}, issn = {1532-8600}, doi = {10.1016/j.metabol.2013.07.008}, author = {Danziger, John and Biggs, Mary L and Niemi, Matt and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and de Boer, Ian H and Siscovick, David S and Kestenbaum, Bryan and Mukamal, Kenneth J} } @article {6080, title = {Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults.}, journal = {Lipids}, volume = {48}, year = {2013}, month = {2013 Nov}, pages = {1169-75}, abstract = {

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p~<=~0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p~=~0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency~=~16~\%; p~=~0.001) and African Americans (frequency~=~8~\%; p~=~0.04). The haplotype combined a SNP in the first intron with one in the 3{\textquoteright}untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

}, keywords = {African Americans, Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Cohort Studies, European Continental Ancestry Group, Fatty Acid-Binding Proteins, Female, Gene Frequency, Genetic Association Studies, Haplotypes, Humans, Insulin, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide}, issn = {1558-9307}, doi = {10.1007/s11745-013-3838-7}, author = {Mukamal, Kenneth J and Wilk, Jemma B and Biggs, Mary L and Jensen, Majken K and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Zieman, Susan J and Mozaffarian, Dariush and Psaty, Bruce M and Siscovick, David S and Djouss{\'e}, Luc} } @article {1565, title = {Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study.}, journal = {Eur J Heart Fail}, volume = {15}, year = {2013}, month = {2013 Apr}, pages = {394-9}, chapter = {394}, abstract = {

AIM: To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.

METHODS AND RESULTS: In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95\% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95\% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.

CONCLUSION: An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cohort Studies, Fatty Acid-Binding Proteins, Female, Follow-Up Studies, Glomerular Filtration Rate, Heart Failure, Humans, Male, Proportional Hazards Models, Prospective Studies, Risk Factors, United States, Ventricular Function, Left}, issn = {1879-0844}, doi = {10.1093/eurjhf/hfs196}, author = {Djouss{\'e}, Luc and Bartz, Traci M and Ix, Joachim H and Kochar, Jinesh and Kizer, Jorge R and Gottdiener, John S and Tracy, Russell P and Mozaffarian, Dariush and Siscovick, David S and Mukamal, Kenneth J and Zieman, Susan J} } @article {1552, title = {Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study.}, journal = {Diabetes Care}, volume = {36}, year = {2013}, month = {2013 May}, pages = {1222-8}, abstract = {

OBJECTIVE: Fetuin-A, a hepatic secretory protein that simultaneously inhibits arterial calcification and insulin action, is associated with type 2 diabetes, but its association with cardiovascular disease (CVD) is uncertain. Preliminary studies suggest that the association of fetuin-A with CVD might differ among individuals with or without type 2 diabetes.

RESEARCH DESIGN AND METHODS: This was a prospective study of 3,810 community-living individuals older than 65 years (511 with type 2 diabetes) and free of CVD in 1992 when fetuin-A levels were measured. Participants were followed-up for incident CVD through June 2008.

RESULTS: Mean age was 75 years, and 61\% were women; 1,456 participants had an incident CVD event (248 among individuals with type 2 diabetes). The association of fetuin-A with CVD was modified by type 2 diabetes (P interaction = 0.02). Higher fetuin-A was associated with lower CVD risk among persons without type 2 diabetes [hazard ratio per SD 0.1 g/L higher fetuin-A, 0.93 (95\% CI, 0.88-0.99)], whereas a trend in the opposite direction was observed among individuals with type 2 diabetes, although it was not statistically significant [1.07 (0.93-1.22)]. Among individuals without type 2 diabetes, similar effect modification was observed by obesity and insulin resistance. Consistently, higher fetuin-A was associated with lower CVD risk only in the subgroups without obesity or with HOMA-IR below the median [0.91 (0.85-0.97) and 0.87 (0.79-0.95), respectively].

CONCLUSIONS: The association of fetuin-A with risk of CVD differs among elderly individuals with and without insulin resistance or type 2 diabetes.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Fetuins, Humans, Incidence, Longitudinal Studies, Male, Risk Factors}, issn = {1935-5548}, doi = {10.2337/dc12-1591}, author = {Jensen, Majken K and Bartz, Traci M and Mukamal, Kenneth J and Djouss{\'e}, Luc and Kizer, Jorge R and Tracy, Russell P and Zieman, Susan J and Rimm, Eric B and Siscovick, David S and Shlipak, Michael and Ix, Joachim H} } @article {5995, title = {Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.}, journal = {Diabetes Care}, volume = {36}, year = {2013}, month = {2013 Oct}, pages = {3121-7}, abstract = {

OBJECTIVE: Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5\%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS: Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993.

RESULTS: Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95\% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95\% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant.

CONCLUSIONS: Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

}, keywords = {alpha-2-HS-Glycoprotein, Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Female, Genotype, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1935-5548}, doi = {10.2337/dc12-2323}, author = {Jensen, Majken K and Bartz, Traci M and Djouss{\'e}, Luc and Kizer, Jorge R and Zieman, Susan J and Rimm, Eric B and Siscovick, David S and Psaty, Bruce M and Ix, Joachim H and Mukamal, Kenneth J} } @article {5845, title = {Insulin resistance and risk of incident heart failure: Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 May}, pages = {364-70}, abstract = {

BACKGROUND: Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance as compared with matched controls. Insulin resistance leads to structural abnormalities in the heart, such as increased left atrial size, left ventricular mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether insulin resistance precedes the development of HF or whether the relationship between insulin resistance and HF is present among adults with HF caused by nonischemic heart disease.

METHODS AND RESULTS: We examined 4425 participants (60\% women) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes mellitus at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry. There were 1216 cases of incident HF (1103 without antecedent myocardial infarction) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (hazard ratio, 1.10; 95\% confidence interval, 1.05-1.15, per SD change) when adjusted for age, sex, race, field center, physical activity, smoking, alcohol intake, high-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent myocardial infarction (hazard ratio, 1.10; 95\% confidence interval, 1.05-1.15). Measures of left atrial size, left ventricular mass, and peak A velocity at baseline were associated both with fasting insulin levels and with HF; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (hazard ratio, 1.08; 95\% confidence interval, 1.03-1.14 per 1-SD increase in fasting insulin).

CONCLUSIONS: Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in Cardiovascular Health Study participants, including those without an antecedent myocardial infarction.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Female, Heart Atria, Heart Failure, Heart Ventricles, Humans, Incidence, Insulin, Insulin Resistance, Male, Middle Aged, Myocardial Infarction, Organ Size, Proportional Hazards Models, Prospective Studies}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.112.000022}, author = {Banerjee, Dipanjan and Biggs, Mary L and Mercer, Laina and Mukamal, Kenneth and Kaplan, Robert and Barzilay, Joshua and Kuller, Lewis and Kizer, Jorge R and Djouss{\'e}, Luc and Tracy, Russell and Zieman, Susan and Lloyd-Jones, Donald and Siscovick, David and Carnethon, Mercedes} } @article {6211, title = {Plasma Fatty Acid binding protein 4 and risk of sudden cardiac death in older adults.}, journal = {Cardiol Res Pract}, volume = {2013}, year = {2013}, month = {2013}, pages = {181054}, abstract = {

Although fatty acid binding protein 4 (FABP4) may increase risk of diabetes and exert negative cardiac inotropy, it is unknown whether plasma concentrations of FABP4 are associated with incidence of sudden cardiac death (SCD). We prospectively analyzed data on 4,560 participants of the Cardiovascular Health Study. FABP4 was measured at baseline using ELISA, and SCD events were adjudicated through review of medical records. We used Cox proportional hazards to estimate effect measures. During a median followup of 11.8 years, 146 SCD cases occurred. In a multivariable model adjusting for demographic, lifestyle, and metabolic factors, relative risk of SCD associated with each higher standard deviation (SD) of plasma FABP4 was 1.15 (95\% CI: 0.95-1.38), P = 0.15. In a secondary analysis stratified by prevalent diabetes status, FABP4 was associated with higher risk of SCD in nondiabetic participants, (RR per SD higher FABP4: 1.33 (95\% CI: 1.07-1.65), P = 0.009) but not in diabetic participants (RR per SD higher FABP4: 0.88 (95\% CI: 0.62-1.27), P = 0.50), P for diabetes-FABP4 interaction 0.049. In summary, a single measure of plasma FABP4 obtained later in life was not associated with the risk of SCD in older adults overall. Confirmation of our post-hoc results in nondiabetic people in other studies is warranted.

}, issn = {2090-8016}, doi = {10.1155/2013/181054}, author = {Djouss{\'e}, Luc and Maziarz, Marlena and Biggs, Mary L and Ix, Joachim H and Zieman, Susan J and Kizer, Jorge R and Lemaitre, Rozenn N and Mozaffarian, Dariush and Tracy, Russell P and Mukamal, Kenneth J and Siscovick, David S and Sotoodehnia, Nona} } @article {6064, title = {Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {6}, year = {2013}, month = {2013 Sep 01}, pages = {964-9}, abstract = {

BACKGROUND: Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).

METHODS AND RESULTS: To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12\% (95\% confidence interval, 6\%-19\%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95\% confidence interval, 1.09-1.23]).

CONCLUSIONS: A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Comorbidity, Fatty Acids, Nonesterified, Female, Heart Failure, Humans, Incidence, Kaplan-Meier Estimate, Linear Models, Male, Multivariate Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Time Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.113.000521}, author = {Djouss{\'e}, Luc and Benkeser, David and Arnold, Alice and Kizer, Jorge R and Zieman, Susan J and Lemaitre, Rozenn N and Tracy, Russell P and Gottdiener, John S and Mozaffarian, Dariush and Siscovick, David S and Mukamal, Kenneth J and Ix, Joachim H} } @article {6139, title = {Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults.}, journal = {J Clin Endocrinol Metab}, volume = {98}, year = {2013}, month = {2013 Jan}, pages = {255-63}, abstract = {

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

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

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

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

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

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

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

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

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

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

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

}, keywords = {Aged, Albumins, Antihypertensive Agents, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Creatinine, Female, Glomerular Filtration Rate, Glycation End Products, Advanced, Humans, Immunoassay, Incidence, Lysine, Male, Oxidative Stress, Proportional Hazards Models, Stroke, Treatment Outcome}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2014.04.013}, author = {Kizer, Jorge R and Benkeser, David and Arnold, Alice M and Ix, Joachim H and Mukamal, Kenneth J and Djouss{\'e}, Luc and Tracy, Russell P and Siscovick, David S and Psaty, Bruce M and Zieman, Susan J} } @article {6337, title = {Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS).}, journal = {Am Heart J}, volume = {167}, year = {2014}, month = {2014 May}, pages = {723-8.e2}, abstract = {

BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited.

METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor β1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years.

RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 μg/L), adjusted hazard ratios (95\% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor β1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk.

CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Cardiomyopathies, Electrocardiography, Enzyme-Linked Immunosorbent Assay, Female, Fibrosis, Follow-Up Studies, Humans, Incidence, Male, Peptide Fragments, Procollagen, Prospective Studies, Risk Factors, Time Factors, Transforming Growth Factor beta1, United States}, issn = {1097-6744}, doi = {10.1016/j.ahj.2014.01.010}, author = {Rosenberg, Michael A and Maziarz, Marlena and Tan, Alex Y and Glazer, Nicole L and Zieman, Susan J and Kizer, Jorge R and Ix, Joachim H and Djouss{\'e}, Luc and Siscovick, David S and Heckbert, Susan R and Mukamal, Kenneth J} } @article {6375, title = {Circulating levels of carboxy-methyl-lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study.}, journal = {J Bone Miner Res}, volume = {29}, year = {2014}, month = {2014}, pages = {1061-6}, abstract = {

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy-methyl-lysine (CML) are associated with risk of hip fracture.We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68{\textendash}102 years; 39.8\% male) for a median of 9.22 years (range, 0.01{\textendash}12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD)measurement. There were 348 hip fractures during follow-up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant-years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95\% confidence interval [CI], 1.16{\textendash}1.40]; p<0.001). Sequential adjustment for age, gender, race/ethnicity,body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95\% CI, 1.05{\textendash}1.31; p=0.006).In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures.

}, keywords = {Age Factors, Aged, Female, Follow-Up Studies, Glycation End Products, Advanced, Hip Fractures, Humans, Incidence, Lysine, Male, Prospective Studies, Retrospective Studies, Risk Factors}, issn = {1523-4681}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Zieman, Susan J and Kizer, Jorge R and Djouss{\'e}, Luc and Ix, Joachim H and Tracy, Russell P and Siscovick, David S and Cauley, Jane A and Mukamal, Kenneth J} } @article {6000, title = {Do changes in circulating biomarkers track with each other and with functional changes in older adults?}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {69}, year = {2014}, month = {2014 Feb}, pages = {174-81}, abstract = {

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

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

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

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

}, keywords = {Adiponectin, Aged, Aged, 80 and over, Aging, Biomarkers, Cholesterol, Cognition, Cohort Studies, Dehydroepiandrosterone Sulfate, Female, Gait, Hand Strength, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Interleukin-6, Male, Neuropsychological Tests, Psychomotor Performance, Time Factors}, issn = {1758-535X}, doi = {10.1093/gerona/glt088}, author = {Sanders, Jason L and Ding, Victoria and Arnold, Alice M and Kaplan, Robert C and Cappola, Anne R and Kizer, Jorge R and Boudreau, Robert M and Cushman, Mary and Newman, Anne B} } @article {6541, title = {Fibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Aug}, pages = {583-9}, abstract = {

BACKGROUND: Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.

METHODS AND RESULTS: We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β{\textquoteright}s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95\% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).

CONCLUSIONS: Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Female, Fibrosis, Heart Failure, Humans, Incidence, Male, Myocardial Infarction, Peptide Fragments, Procollagen, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Time Factors, Transforming Growth Factor beta, United States}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001610}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Sicovick, David S and Tracy, Russell P and Mukamal, Kenneth J} } @article {6336, title = {Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {179}, year = {2014}, month = {2014 Jun 01}, pages = {1331-9}, abstract = {

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95\% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cause of Death, Female, Fibrosis, Follow-Up Studies, Humans, Likelihood Functions, Male, Multivariate Analysis, Peptide Fragments, Procollagen, Proportional Hazards Models, Prospective Studies, Risk Factors, Transforming Growth Factor beta}, issn = {1476-6256}, doi = {10.1093/aje/kwu067}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Zieman, Susan J and Mukamal, Kenneth J} } @article {6212, title = {Plasma free fatty acids and risk of stroke in the Cardiovascular Health Study.}, journal = {Int J Stroke}, volume = {9}, year = {2014}, month = {2014 Oct}, pages = {917-20}, abstract = {

BACKGROUND: Although free fatty acids have been positively associated with risk factors for stroke, the role of plasma free fatty acids in the development of stroke has not been elucidated in older adults.

AIMS: We sought to examine the association between plasma free fatty acids and incident stroke.

METHODS: Prospective cohort of 4369 men and women>=65 years of age in the Cardiovascular Health Study. Plasma levels of free fatty acids were measured at the 1992-1993 examination and stroke events were adjudicated by a committee of experts including neurologists and neuroradiologists. Cox regression was used to estimate the relative risk of stroke associated with free fatty acids concentrations.

RESULTS: The average age among participants was 75{\textpm}5{\textperiodcentered}2 years. During a median follow-up of 11{\textperiodcentered}4 years, 732 incident strokes occurred. The crude incidence rates of stroke were 14{\textperiodcentered}5, 14{\textperiodcentered}9, and 17{\textperiodcentered}6 per 1000 person-years across increasing tertiles of plasma free fatty acids. The adjusted hazard ratio (95\% confidence interval) for incident stroke was 1{\textperiodcentered}05 (0{\textperiodcentered}97-1{\textperiodcentered}14) per standard deviation increase in plasma free fatty acids. Restriction to ischemic stroke did not alter the results [hazard ratio (95\% confidence interval): 1{\textperiodcentered}04 (0{\textperiodcentered}96-1{\textperiodcentered}14) per standard deviation higher free fatty acids], and there was no effect modification by adiposity (P interaction=0{\textperiodcentered}18) or by diabetes (P interaction=0{\textperiodcentered}15).

CONCLUSION: Our data did not show an association of plasma free fatty acids with incident stroke among community dwelling older adults.

}, keywords = {Aged, Biomarkers, Brain Ischemia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Prospective Studies, Risk, Stroke}, issn = {1747-4949}, doi = {10.1111/ijs.12216}, author = {Khawaja, Owais and Maziarz, Marlena and Biggs, Mary L and Longstreth, William T and Ix, Joachim H and Kizer, Jorge R and Zieman, Susan and Tracy, Russell P and Mozaffarian, Dariush and Mukamal, Kenneth J and Siscovick, David S and Djouss{\'e}, Luc} } @article {6584, title = {Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {114}, year = {2014}, month = {2014 Sep 15}, pages = {843-8}, abstract = {

Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95\% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95\% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95\% CI 1.08 to 1.26 for men; HR 1.02, 95\% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.

}, keywords = {Age Distribution, Age Factors, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Cause of Death, Fatty Acid-Binding Proteins, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Health Status, Humans, Male, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Survival Rate, Time Factors, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2014.06.012}, author = {Miedema, Michael D and Maziarz, Marlena and Biggs, Mary L and Zieman, Susan J and Kizer, Jorge R and Ix, Joachim H and Mozaffarian, Dariush and Tracy, Russell P and Psaty, Bruce M and Siscovick, David S and Mukamal, Kenneth J and Djouss{\'e}, Luc} } @article {6137, title = {Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults >=65 years of age (from the Cardiovascular Health study).}, journal = {Am J Cardiol}, volume = {113}, year = {2014}, month = {2014 Jan 15}, pages = {328-34}, abstract = {

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

}, keywords = {Adiponectin, Age of Onset, Aged, Biomarkers, Cross-Sectional Studies, Echocardiography, Doppler, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Prognosis, Prospective Studies, Recurrence, Severity of Illness Index, United States, Ventricular Function, Left}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2013.09.027}, author = {Karas, Maria G and Benkeser, David and Arnold, Alice M and Bartz, Traci M and Djouss{\'e}, Luc and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Tracy, Russell P and Mantzoros, Christos S and Gottdiener, John S and deFilippi, Christopher R and Kizer, Jorge R} } @article {6338, title = {Separate prediction of intracerebral hemorrhage and ischemic stroke.}, journal = {Neurology}, volume = {82}, year = {2014}, month = {2014 May 20}, pages = {1804-12}, abstract = {

OBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).

METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45\% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38\% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41\% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions{\textquoteright} performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.

RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.

CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual{\textquoteright}s stroke risk.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Body Mass Index, Brain Ischemia, Cholesterol, Female, Humans, Incidence, Intracranial Hemorrhages, Male, Middle Aged, Models, Statistical, Predictive Value of Tests, Risk Assessment, Risk Factors, Stroke}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000000427}, author = {Ferket, Bart S and van Kempen, Bob J H and Wieberdink, Renske G and Steyerberg, Ewout W and Koudstaal, Peter J and Hofman, Albert and Shahar, Eyal and Gottesman, Rebecca F and Rosamond, Wayne and Kizer, Jorge R and Kronmal, Richard A and Psaty, Bruce M and Longstreth, W T and Mosley, Thomas and Folsom, Aaron R and Hunink, M G Myriam and Ikram, M Arfan} } @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 {6277, title = {Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study.}, journal = {Clin Endocrinol (Oxf)}, volume = {81}, year = {2014}, month = {2014 Nov}, pages = {746-53}, abstract = {

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

DESIGN: Cohort study.

PARTICIPANTS: Elderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010.

MEASUREMENTS: Adjudicated ischaemic stroke.

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

CONCLUSIONS: Dihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men.

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

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

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

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

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

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

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

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cause of Death, Dihydrotestosterone, Humans, Incidence, Longitudinal Studies, Male, Mortality, Residence Characteristics, Risk Factors, Testosterone}, issn = {1945-7197}, doi = {10.1210/jc.2013-3576}, author = {Shores, Molly M and Biggs, Mary L and Arnold, Alice M and Smith, Nicholas L and Longstreth, W T and Kizer, Jorge R and Hirsch, Calvin H and Cappola, Anne R and Matsumoto, Alvin M} } @article {6666, title = {Association of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study.}, journal = {J Bone Miner Res}, volume = {30}, year = {2015}, month = {2015 Aug}, pages = {1394-402}, abstract = {

Fetuin-A, a serum protein that regulates calcium mineralization, has been associated with bone mineral density (BMD) in several cross-sectional human studies, suggesting a possible beneficial effect on clinically important measures of bone health. Fetuin-A and incidence of subsequent fracture was assessed in 4714 men and women >=65 years of age. Proportional hazards models were used to estimate risk of incident hip (hospital discharge ICD-9 codes) and composite fracture (hip, pelvis, humerus, or proximal forearm; hospital discharge ICD-9 codes and Medicare claims data). A total of 576 participants had an incident hip fracture (median follow-up 11.2 years) and 768 had an incident composite fracture (median follow-up 6.9 years). In unadjusted analyses, there was no association between fetuin-A (per SD increase) and risk of hip fracture (hazard ratio [HR], 0.96; 95\% CI, 0.88 to 1.05) or composite fracture (HR, 0.99; 95\% CI, 0.92 to 1.06). Results were not significantly changed after adjustment for potential confounding variables. Analyses modeling fetuin-A in quartiles or within a subset with available BMD measures also showed no statistically significant association with risk of hip or composite fracture. Though fetuin-A was positively associated with areal BMD in partially adjusted models (total hip: β, 0.013 g/cm(2) ; 95\% CI, 0.005 to 0.021; femoral neck: β, 0.011 g/cm(2) ; 95\% CI, 0.004 to 0.018; and lumbar spine: β, 0.007 g/cm(2) ; 95\% CI, 0.001 to 0.028), these associations were no longer significant after further adjustment for BMI and in final multivariate models. In this large sample of community-dwelling older adults, a small positive association between fetuin-A and areal BMD appeared attributable to confounding variables and we found no evidence of an association between fetuin-A and risk of clinical fracture.

}, keywords = {Adult, Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Bone Density, Cross-Sectional Studies, Female, Follow-Up Studies, Fractures, Bone, Humans, Incidence, Male, Models, Biological}, issn = {1523-4681}, doi = {10.1002/jbmr.2475}, author = {Fink, Howard A and B{\r u}zkov{\'a}, Petra and Garimella, Pranav S and Mukamal, Kenneth J and Cauley, Jane A and Kizer, Jorge R and Barzilay, Joshua I and Jalal, Diana I and Ix, Joachim H} } @article {6805, title = {Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study.}, journal = {Metabolism}, volume = {64}, year = {2015}, month = {2015 Oct}, pages = {1316-23}, abstract = {

AIM: Fibrosis is one postulated pathway by which diabetes produces cardiac and other systemic complications. Our aim was to determine which metabolic parameters are associated with circulating fibrosis-related biomarkers transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP).

METHODS: We used linear regression to determine the cross-sectional associations of diverse metabolic parameters, including fasting glucose, fasting insulin, body mass index, fatty acid binding protein 4, and non-esterified fatty acids, with circulating levels of TGF-β (n = 1559) and PIIINP (n = 3024) among community-living older adults in the Cardiovascular Health Study.

RESULTS: Among the main metabolic parameters we examined, only fasting glucose was associated with TGF-β (P = 0.03). In contrast, multiple metabolic parameters were associated with PIIINP, including fasting insulin, body mass index, and non-esterified fatty acids (P<0.001, P<0.001, P=0.001, respectively). These associations remained statistically significant after mutual adjustment, except the association between BMI and PIIINP.

CONCLUSIONS: Isolated hyperglycemia is associated with higher serum concentrations of TGF-β, while a broader phenotype of insulin resistance is associated with higher serum PIIINP. Whether simultaneous pharmacologic targeting of these two metabolic phenotypes can synergistically reduce the risk of cardiac and other manifestations of fibrosis remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Blood Glucose, Cardiovascular System, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Fatty Acids, Nonesterified, Female, Fibrosis, Health, Humans, Insulin, Insulin Resistance, Male, Metabolic Diseases, Peptide Fragments, Procollagen, Transforming Growth Factor beta}, issn = {1532-8600}, doi = {10.1016/j.metabol.2015.07.013}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and King, George L and Mukamal, Ken J} } @article {6679, title = {Atherosclerotic cardiovascular disease in older adults with diabetes mellitus.}, journal = {Clin Geriatr Med}, volume = {31}, year = {2015}, month = {2015 Feb}, pages = {29-39, vii}, abstract = {

Diabetes mellitus exerts a strong effect on atherosclerotic cardiovascular disease risk into older age (beyond ages 70-74 years). This effect is particularly noticeable with regard to coronary artery disease and cerebral microvascular disease. Thus, diabetes mellitus in older adults deserves the same careful medical attention as it does in middle age.

}, keywords = {Age Factors, Aged, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, Humans, Male, Risk Factors, Survival Rate}, issn = {1879-8853}, doi = {10.1016/j.cger.2014.09.001}, author = {Barzilay, Joshua I and Mukamal, Kenneth J and Kizer, Jorge R} } @article {6768, title = {Burden of Comorbidities and Functional and Cognitive Impairments in Elderly Patients at the Initial Diagnosis of Heart Failure and Their Impact on Total Mortality: The Cardiovascular Health Study.}, journal = {JACC Heart Fail}, volume = {3}, year = {2015}, month = {2015 Jul}, pages = {542-50}, abstract = {

OBJECTIVES: The purpose of this study was to determine the prevalence of clinically relevant comorbidities and measures of physical and cognitive impairment in elderly persons with incident heart failure (HF).

BACKGROUND: Comorbidities and functional and cognitive impairments are common in the elderly and often associated with greater mortality risk.

METHODS: We examined the prevalence of 9 comorbidities and 4 measures of functional and cognitive impairments in 558 participants from the Cardiovascular Health Study who developed incident HF between 1990 and 2002. Participants were followed prospectively until mid-2008 to determine their mortality risk.

RESULTS: Mean age of participants was 79.2 {\textpm} 6.3 years with 52\% being men. Sixty percent of participants had >=3 comorbidities, and only 2.5\% had none. Twenty-two percent and 44\% of participants had >=1 activity of daily living (ADL) and >=1 instrumental activity of daily living (IADL) impaired respectively. Seventeen percent of participants had cognitive impairment (modified mini-mental state exam score <80, scores range between 0 and 100). During follow up, 504 participants died, with 1-, 5-, and 10-year mortality rates of 19\%, 56\%, and 83\%, respectively. In a multivariable-adjusted model, the following were significantly associated with greater total mortality risk: diabetes mellitus (hazard ratio [HR]: 1.64; 95\% confidence interval [CI]: 1.33 to 2.03), chronic kidney disease (HR: 1.32; 95\% CI: 1.07 to 1.62 for moderate disease; HR: 3.00; 95\% CI: 1.82 to 4.95 for severe), cerebrovascular disease (HR: 1.53; 95\% CI: 1.22 to 1.92), depression (HR: 1.44; 95\% CI: 1.09 to 1.90), functional impairment (HR: 1.30; 95\% CI: 1.04 to 1.63 for 1 IADL impaired; HR: 1.49; 95\% CI: 1.07 to 2.04 for >=2 IADL impaired), and cognitive impairment (HR: 1.33; 95\% CI: 1.02 to 1.73). Other comorbidities (hypertension, coronary heart disease, peripheral arterial disease, atrial fibrillation, and obstructive airway disease) and measures of functional impairments (ADLs and 15-ft walk time) were not associated with mortality.

CONCLUSIONS: Elderly patients with incident HF have a high burden of comorbidities and functional and cognitive impairments. Some of these conditions are associated with greater mortality risk.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Atrial Fibrillation, Cognition Disorders, Cohort Studies, Comorbidity, Coronary Disease, Female, Heart Failure, Humans, Hypertension, Incidence, Longitudinal Studies, Male, Peripheral Arterial Disease, Physical Fitness, Prevalence, Proportional Hazards Models, Pulmonary Disease, Chronic Obstructive}, issn = {2213-1787}, doi = {10.1016/j.jchf.2015.03.004}, author = {Murad, Khalil and Goff, David C and Morgan, Timothy M and Burke, Gregory L and Bartz, Traci M and Kizer, Jorge R and Chaudhry, Sarwat I and Gottdiener, John S and Kitzman, Dalane W} } @article {6737, title = {Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 May}, pages = {902-9}, abstract = {

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.

DESIGN: Retrospective analysis of a cohort study.

SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).

MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).

RESULTS: At baseline, mean age was 76.3{\textpm}3.6, and 18.5\% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3\% for IGF-I, 59.7\% for IGFBP-1, -13.4\% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7\% for IGF-I, 25.6\% for IGFBP-1, -6.4\% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.

CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.

}, keywords = {Aged, Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Retrospective Studies}, issn = {1532-5415}, doi = {10.1111/jgs.13390}, author = {Aneke-Nash, Chino S and Parrinello, Christina M and Rajpathak, Swapnil N and Rohan, Thomas E and Strotmeyer, Elsa S and Kritchevsky, Stephen B and Psaty, Bruce M and B{\r u}zkov{\'a}, Petra and Kizer, Jorge R and Newman, Anne B and Strickler, Howard D and Kaplan, Robert C} } @article {6853, title = {Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies.}, journal = {Atherosclerosis}, volume = {243}, year = {2015}, month = {2015 Nov}, pages = {44-52}, abstract = {

BACKGROUND AND AIMS: Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is unclear. We used two common genetic variants in the fetuin-A gene (AHSG) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification).

METHODS: Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992-1993.

RESULTS: Among Caucasians, both rs2248690 and rs4917 were associated with 12\% lower fetuin-A concentrations per minor allele (P~<~0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95\% CI: 1.00-1.26) for rs2248690 and 1.02 (0.91-1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95\% CI: 0.70-1.00) for rs2248690 and 0.97 (95\% CI: 0.82-1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93-1.34) and 1.06 (0.93-1.20) for rs2248690 and rs4917, respectively (p heterogeneity 0.005 and 0.0048).

CONCLUSION: Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.

}, keywords = {Aged, Aged, 80 and over, alpha-2-HS-Glycoprotein, Carotid Intima-Media Thickness, Coronary Vessels, Female, Genetic Variation, Genotype, Heart Diseases, Humans, Insulin Resistance, Longitudinal Studies, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Vascular Calcification}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.08.031}, author = {Laugsand, Lars E and Ix, Joachim H and Bartz, Traci M and Djouss{\'e}, Luc and Kizer, Jorge R and Tracy, Russell P and Dehghan, Abbas and Rexrode, Kathryn and Lopez, Oscar L and Rimm, Eric B and Siscovick, David S and O{\textquoteright}Donnell, Christopher J and Newman, Anne and Mukamal, Kenneth J and Jensen, Majken K} } @article {6665, title = {Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {239}, year = {2015}, month = {2015 Apr}, pages = {539-46}, abstract = {

OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.

METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.

RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]~=~1.36 per doubling of TGF-β, 95\% confidence interval [CI]~=~1.04, 1.78) and retinal venular diameter (1.63~μm per doubling of TGF-β, CI~=~0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102~mm per doubling of PIIINP, CI~=~0.029, 0.174) and impaired brachial artery reactivity (-0.20\% change per doubling of PIIINP, CI~=~-0.39,~-0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.

CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.

}, keywords = {Aged, Ankle Brachial Index, Biomarkers, Brachial Artery, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cross-Sectional Studies, Female, Fibrosis, Humans, Incidence, Male, Peptide Fragments, Peripheral Arterial Disease, Predictive Value of Tests, Procollagen, Prognosis, Prospective Studies, Retinal Diseases, Risk Factors, Transforming Growth Factor beta, United States, Vasodilation}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.02.020}, author = {Agarwal, Isha and Arnold, Alice and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Jensen, Richard A and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Wong, Tien Y and Mukamal, Kenneth J} } @article {6801, title = {Higher circulating adiponectin levels are associated with increased risk of atrial fibrillation in older adults.}, journal = {Heart}, volume = {101}, year = {2015}, month = {2015 Sep}, pages = {1368-74}, abstract = {

BACKGROUND: Adiponectin has cardioprotective properties, suggesting that lower levels seen in obesity and diabetes could heighten risk of atrial fibrillation (AF). Among older adults, however, higher adiponectin has been linked to greater incidence of adverse outcomes associated with AF, although recent reports have shown this association to be U-shaped. We postulated that higher adiponectin would be linked to increased risk for AF in older adults in a U-shaped manner.

METHODS: We examined the associations of total and high-molecular-weight (HMW) adiponectin with incident AF among individuals free of prevalent cardiovascular disease (CVD) participating in a population-based cohort study of older adults (n=3190; age=74{\textpm}5 years).

RESULTS: During median follow-up of 11.4 years, there were 886 incident AF events. Adjusted cubic splines showed a positive and linear association between adiponectin and incident AF. After adjusting for potential confounders, including amino-terminal pro-B-type natriuretic peptide 1-76, the HR (95\% CI) for AF per SD increase in total adiponectin was 1.14 (1.05 to 1.24), while that for HMW adiponectin was 1.17 (1.08 to 1.27). Additional adjustment for putative mediators, including subclinical CVD, diabetes, lipids and inflammation, did not significantly affect these estimates.

CONCLUSIONS: The present findings demonstrate that higher, not lower, levels of adiponectin are independently associated with increased risk of AF in older adults despite its documented cardiometabolic benefits. Additional work is necessary to determine if adiponectin is a marker of failed counter-regulatory pathways or whether this hormone is directly harmful in the setting of or as a result of advanced age.

}, keywords = {Adiponectin, Age Factors, Aged, Aged, 80 and over, Aging, Atrial Fibrillation, Biomarkers, Female, Humans, Incidence, Linear Models, Male, Multivariate Analysis, Natriuretic Peptide, Brain, Peptide Fragments, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States, Up-Regulation}, issn = {1468-201X}, doi = {10.1136/heartjnl-2014-307015}, author = {Macheret, Fima and Bartz, Traci M and Djouss{\'e}, Luc and Ix, Joachim H and Mukamal, Kenneth J and Zieman, Susan J and Siscovick, David S and Tracy, Russell P and Heckbert, Susan R and Psaty, Bruce M and Kizer, Jorge R} } @article {6663, title = {Plasma phospholipid very-long-chain saturated fatty acids and incident diabetes in older adults: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 May}, pages = {1047-54}, abstract = {

BACKGROUND: Circulating saturated fatty acids (SFAs) are integrated biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. In epidemiologic studies, circulating levels of palmitic acid (16:0) are associated with diabetes; however, very-long-chain SFAs (VLSFAs), with 20 or more carbons, differ from palmitic acid in their biological activities, and little is known of the association of circulating VLSFA with diabetes.

OBJECTIVE: By using data from the Cardiovascular Health Study, we examined the associations of plasma phospholipid VLSFA levels measured at baseline with subsequent incident diabetes.

DESIGN: A total of 3179 older adults, with a mean age of 75 y at study baseline (1992-1993), were followed through 2011. We used multiple proportional hazards regression to examine the associations of arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with diabetes.

RESULTS: Baseline levels of each VLSFA were cross-sectionally associated with lower triglyceride levels and lower circulating palmitic acid. We identified 284 incident diabetes cases during follow-up. Compared with the lowest quartile, levels of arachidic acid in the highest quartile of the fatty acid distribution were associated with a 47\% lower risk of diabetes (95\% CI: 23\%, 63\%; P-trend: <0.001), after adjustment for demographics, lifestyle factors, and clinical conditions. In analogous comparisons, levels of behenic and lignoceric acid were similarly associated with 33\% (95\% CI: 6\%, 53\%; P-trend: 0.02) and 37\% (95\% CI: 11\%, 55\%; P-trend: 0.01) lower diabetes risk, respectively. Adjustment for triglycerides and palmitic acid attenuated the associations toward the null, and only the association of arachidic acid remained statistically significant (32\% lower risk for fourth vs. first quartile; P-trend: 0.04).

CONCLUSIONS: These results suggest that circulating VLSFAs are associated with a lower risk of diabetes, and these associations may be mediated by lower triglycerides and palmitic acid. The study highlights the need to distinguish the effects of different SFAs and to explore determinants of circulating VLSFAs. This trial was registered at clinicaltrials.gov as NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cross-Sectional Studies, Diabetes Mellitus, Diet, Eicosanoic Acids, Fatty Acids, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Incidence, Male, Observational Studies as Topic, Palmitic Acid, Phospholipids, Prospective Studies, Risk Factors, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.114.101857}, author = {Lemaitre, Rozenn N and Fretts, Amanda M and Sitlani, Colleen M and Biggs, Mary L and Mukamal, Kenneth and King, Irena B and Song, Xiaoling and Djouss{\'e}, Luc and Siscovick, David S and McKnight, Barbara and Sotoodehnia, Nona and Kizer, Jorge R and Mozaffarian, Dariush} } @article {6400, title = {Potassium and glucose measures in older adults: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {70}, year = {2015}, month = {2015 Feb}, pages = {255-61}, abstract = {

BACKGROUND: We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.

METHODS: Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.

RESULTS: Among 4,754 participants aged >=65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium >=4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of -0.18 (-0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of -0.61 (-0.94, -0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.

CONCLUSIONS: Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.

}, keywords = {Aged, Blood Glucose, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Female, Humans, Insulin, Insulin Resistance, Longitudinal Studies, Male, Multivariate Analysis, Potassium, Potassium, Dietary, Risk Factors, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glu071}, author = {Chatterjee, Ranee and Biggs, Mary L and de Boer, Ian H and Brancati, Frederick L and Svetkey, Laura P and Barzilay, Joshua and Djouss{\'e}, Luc and Ix, Joachim H and Kizer, Jorge R and Siscovick, David S and Mozaffarian, Dariush and Edelman, David and Mukamal, Kenneth J} } @article {6616, title = {Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {153-63}, abstract = {

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95\% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95\% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95\% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

}, keywords = {Aged, Biomarkers, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Incidence, Lipogenesis, Liver, Male, Palmitic Acid, Phospholipids, Prevalence, Proportional Hazards Models, Risk Factors, Stearic Acids, United States, Up-Regulation}, issn = {1938-3207}, doi = {10.3945/ajcn.114.092601}, author = {Ma, Wenjie and Wu, Jason H Y and Wang, Qianyi and Lemaitre, Rozenn N and Mukamal, Kenneth J and Djouss{\'e}, Luc and King, Irena B and Song, Xiaoling and Biggs, Mary L and Delaney, Joseph A and Kizer, Jorge R and Siscovick, David S and Mozaffarian, Dariush} } @article {6702, title = {Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults.}, journal = {Heart Rhythm}, volume = {12}, year = {2015}, month = {2015 May}, pages = {879-85}, abstract = {

BACKGROUND: Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset.

OBJECTIVE: The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF).

METHODS: In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses.

RESULTS: Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0\%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95\% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95\% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF.

CONCLUSION: The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain.

}, keywords = {Aged, Atrial Fibrillation, Biomarkers, Electrocardiography, Female, Heart Failure, Humans, Incidence, Longitudinal Studies, Male, Outpatients, Risk Assessment, Risk Factors, Statistics as Topic, Troponin T, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2015.01.020}, author = {Hussein, Ayman A and Bartz, Traci M and Gottdiener, John S and Sotoodehnia, Nona and Heckbert, Susan R and Lloyd-Jones, Donald and Kizer, Jorge R and Christenson, Robert and Wazni, Oussama and DeFilippi, Christopher} } @article {6660, title = {Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.}, journal = {J Am Soc Nephrol}, volume = {26}, year = {2015}, month = {2015 Oct}, pages = {2494-503}, abstract = {

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged >=65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30\% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age ({\textpm}SD) was 78{\textpm}5 years, mean eGFR was 63{\textpm}18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22\% higher odds of CKD progression (adjusted odds ratio, 1.22; 95\% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

}, keywords = {Aged, Cardiovascular Diseases, Case-Control Studies, Disease Progression, Female, Heart Failure, Humans, Kidney Failure, Chronic, Male, Peptide Fragments, Procollagen, Prospective Studies, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2014070696}, author = {Ix, Joachim H and Biggs, Mary L and Mukamal, Kenneth and Djouss{\'e}, Luc and Siscovick, David and Tracy, Russell and Katz, Ronit and Delaney, Joseph A and Chaves, Paulo and Rifkin, Dena E and Hughes-Austin, Jan M and Garimella, Pranav S and Sarnak, Mark J and Shlipak, Michael G and Kizer, Jorge R} } @article {7120, title = {Association of inflammatory, lipid and mineral markers with cardiac calcification in older adults.}, journal = {Heart}, year = {2016}, month = {2016 Jul 13}, abstract = {

OBJECTIVE: Calcification of the aortic valve and adjacent structures involves inflammatory, lipid and mineral metabolism pathways. We hypothesised that circulating biomarkers reflecting these pathways are associated with cardiac calcification in older adults.

METHODS: We investigated the associations of various biomarkers with valvular and annular calcification in the Cardiovascular Health Study. Of the 5888 participants, up to 3585 were eligible after exclusions for missing biomarker, covariate or echocardiographic data. We evaluated analytes reflecting lipid (lipoprotein (Lp) (a), Lp-associated phospholipase A2 (LpPLA2) mass and activity), inflammatory (interleukin-6, soluble (s) CD14) and mineral metabolism (fetuin-A, fibroblast growth factor (FGF)-23) pathways that were measured within 5 years of echocardiography. The relationships of plasma biomarkers with aortic valve calcification (AVC), aortic annular calcification (AAC) and mitral annular calcification (MAC) were assessed with relative risk (RR) regression.

RESULTS: Calcification was prevalent: AVC 59\%, AAC 45\% and MAC 41\%. After adjustment, Lp(a), LpPLA2 mass and activity and sCD14 were positively associated with AVC. RRs for AVC per SD (95\% CI) were as follows: Lp(a), 1.051 (1.022 to 1.081); LpPLA2 mass, 1.036 (1.006 to 1.066) and LpPLA2 activity, 1.037 (1.004 to 1.071); sCD14, 1.039 (1.005 to 1.073). FGF-23 was positively associated with MAC, 1.040 (1.004 to 1.078) and fetuin-A was negatively associated, 0.949 (0.911 to 0.989). No biomarkers were significantly associated with AAC.

CONCLUSION: This study shows novel associations of circulating FGF-23 and fetuin-A with MAC, and LpPLA2 and sCD14 with AVC, confirming that previously reported for Lp(a). Further investigation of Lp and inflammatory pathways may provide added insight into the aetiology of AVC, while study of phosphate regulation may illuminate the pathogenesis of MAC.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2016-309404}, author = {Bortnick, Anna E and Bartz, Traci M and Ix, Joachim H and Chonchol, Michel and Reiner, Alexander and Cushman, Mary and Owens, David and Barasch, Eddy and Siscovick, David S and Gottdiener, John S and Kizer, Jorge R} } @article {7133, title = {Effects of Disease Burden and Functional Adaptation on Morbidity and Mortality on Older Adults.}, journal = {J Am Geriatr Soc}, volume = {64}, year = {2016}, month = {2016 Jun}, pages = {1242-9}, abstract = {

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

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

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older.

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

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

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

}, issn = {1532-5415}, doi = {10.1111/jgs.14163}, author = {Sanders, Jason L and Arnold, Alice M and Hirsch, Calvin H and Thielke, Stephen M and Kim, Dae and Mukamal, Kenneth J and Kizer, Jorge R and Ix, Joachim H and Kaplan, Robert C and Kritchevsky, Stephen B and Newman, Anne B} } @article {7167, title = {Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.}, journal = {Diabetes}, volume = {65}, year = {2016}, month = {2016 Oct}, pages = {3200-11}, abstract = {

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 {\texttimes} 10(-11)), rs12454712 (BCL2; P = 2.7 {\texttimes} 10(-8)), and rs10506418 (FAM19A2; P = 1.9 {\texttimes} 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

}, issn = {1939-327X}, doi = {10.2337/db16-0199}, author = {Walford, Geoffrey A and Gustafsson, Stefan and Rybin, Denis and Stan{\v c}{\'a}kov{\'a}, Alena and Chen, Han and Liu, Ching-Ti and Hong, Jaeyoung and Jensen, Richard A and Rice, Ken and Morris, Andrew P and M{\"a}gi, Reedik and T{\"o}njes, Anke and Prokopenko, Inga and Kleber, Marcus E and Delgado, Graciela and Silbernagel, G{\"u}nther and Jackson, Anne U and Appel, Emil V and Grarup, Niels and Lewis, Joshua P and Montasser, May E and Landenvall, Claes and Staiger, Harald and Luan, Jian{\textquoteright}an and Frayling, Timothy M and Weedon, Michael N and Xie, Weijia and Morcillo, Sonsoles and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and Biggs, Mary L and Chen, Yii-Der Ida and Corbaton-Anchuelo, Arturo and F{\ae}rch, Kristine and G{\'o}mez-Zumaquero, Juan Miguel and Goodarzi, Mark O and Kizer, Jorge R and Koistinen, Heikki A and Leong, Aaron and Lind, Lars and Lindgren, Cecilia and Machicao, Fausto and Manning, Alisa K and Mart{\'\i}n-N{\'u}{\~n}ez, Gracia Mar{\'\i}a and Rojo-Mart{\'\i}nez, Gemma and Rotter, Jerome I and Siscovick, David S and Zmuda, Joseph M and Zhang, Zhongyang and Serrano-R{\'\i}os, Manuel and Smith, Ulf and Soriguer, Federico and Hansen, Torben and J{\o}rgensen, Torben J and Linnenberg, Allan and Pedersen, Oluf and Walker, Mark and Langenberg, Claudia and Scott, Robert A and Wareham, Nicholas J and Fritsche, Andreas and H{\"a}ring, Hans-Ulrich and Stefan, Norbert and Groop, Leif and O{\textquoteright}Connell, Jeff R and Boehnke, Michael and Bergman, Richard N and Collins, Francis S and Mohlke, Karen L and Tuomilehto, Jaakko and M{\"a}rz, Winfried and Kovacs, Peter and Stumvoll, Michael and Psaty, Bruce M and Kuusisto, Johanna and Laakso, Markku and Meigs, James B and Dupuis, Jos{\'e}e and Ingelsson, Erik and Florez, Jose C} } @article {7258, title = {Insulinlike growth factor binding protein-1 and ghrelin predict health outcomes among older adults: CHS cohort.}, journal = {J Clin Endocrinol Metab}, year = {2016}, month = {2016 Nov 07}, pages = {jc20162779}, abstract = {

CONTEXT: Multiple diseases may explain the association of the growth hormone / insulinlike growth factor-I (GH/IGF-I) axis with longevity.

OBJECTIVE: To relate circulating GH/IGF-I system protein levels with major health events.

DESIGN: Cohort study Setting: Four US communities Participants: Adults (n=2268) 65 years and older free of diabetes and cardiovascular disease.

MEASUREMENTS: We assessed insulinlike growth factor binding protein-1 (IGFBP-1) and ghrelin in fasting and 2-hour oral glucose tolerance test (OGTT) blood samples, as well as fasting IGF-I and IGFBP-3. Hazard ratios for mortality and a composite outcome for first incident myocardial infarction, stroke, heart failure, hip fracture, or death were adjusted for sociodemographic, behavioral, and physiologic covariates.

RESULTS: During 13,930 person-years of follow-up, 48.1\% individuals sustained one or more components of the composite outcome and 31.8\% died. Versus the lowest quartiles, the highest quartiles of fasting and 2-h ghrelin were associated with a 27\% higher (95\% CI: 6\%, 53\%) and 39\% higher (95\% CI: 14\%, 71\%) risks of the composite outcome, respectively. The highest quartile of 2-h IGFBP-1 was associated with 35\% higher (95\% CI: 1\%, 52\%) risk of the composite endpoint. Similarly, higher mortality was significantly associated with higher fasting and 2-h ghrelin level, and with 2-h IGFBP-1 level. When examined together, 2-h post-OGTT levels of IGFBP-1 and ghrelin tended to predict outcomes better than fasting levels.

CONCLUSIONS: Circulating IGFBP-1 and ghrelin measured during an OGTT predict major health events and death in older adults, which may explain the influence of the GH-IGF-axis on lifespan and health.

}, issn = {1945-7197}, doi = {10.1210/jc.2016-2779}, author = {Kaplan, Robert C and Strizich, Garrett and Aneke-Nash, Chino and Dominguez-Islas, Clara and B{\r u}zkov{\'a}, Petra and Strickler, Howard and Rohan, Thomas and Pollak, Michael and Kuller, Lewis and Kizer, Jorge R and Cappola, Anne and Li, Christopher I and Psaty, Bruce M and Newman, Anne} } @article {7242, title = {Longitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study.}, journal = {Metabolism}, volume = {65}, year = {2016}, month = {2016 Oct}, pages = {1489-97}, abstract = {

INTRODUCTION: Natriuretic peptides have a well-recognized role in cardiovascular homeostasis. Recently, higher levels of B-type natriuretic peptide (BNP) have also been associated with decreased risk of diabetes in middle-aged adults. Whether this association persists into older age, where the pathophysiology of diabetes changes, has not been established, nor has its intermediate pathways.

METHODS: We investigated the relationship between N-terminal (NT)-proBNP and incident diabetes in 2359 older adults free of cardiovascular disease or chronic kidney disease in the Cardiovascular Health Study.

RESULTS: We documented 348 incident cases of diabetes over 12.6years of median follow-up. After adjusting for age, sex, race, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL, each doubling of NT-proBNP was associated with a 9\% lower risk of incident diabetes (HR=0.91 [95\% CI: 0.84-0.99]). Additional adjustment for waist circumference, physical activity, estimated glomerular filtration rate or C-reactive protein did not influence the association. Among putative mediators, HDL and triglycerides, adiponectin, and especially homeostasis model assessment of insulin resistance, all appeared to account for a portion of the lower risk associated with NT-proBNP.

CONCLUSION: In older adults without prevalent cardiovascular or kidney disease, higher NT-proBNP is associated with decreased risk of incident diabetes even after adjustment for traditional risk factors. These findings suggest that the metabolic effects of natriuretic peptides persist late in life and offer a potential therapeutic target for prevention of diabetes in older people.

}, issn = {1532-8600}, doi = {10.1016/j.metabol.2016.06.002}, author = {Brutsaert, Erika F and Biggs, Mary L and Delaney, Joseph A and Djouss{\'e}, Luc and Gottdiener, John S and Ix, Joachim H and Kim, Francis and Mukamal, Kenneth J and Siscovick, David S and Tracy, Russell P and de Boer, Ian H and deFilippi, Christopher R and Kizer, Jorge R} } @article {7123, title = {Measures of Body Size and Composition and Risk of Incident Atrial Fibrillation in Older People: The Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {183}, year = {2016}, month = {2016 Jun 1}, pages = {998-1007}, abstract = {

Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95\% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95\% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.

}, issn = {1476-6256}, doi = {10.1093/aje/kwv278}, author = {Karas, Maria G and Yee, Laura M and Biggs, Mary L and Djouss{\'e}, Luc and Mukamal, Kenneth J and Ix, Joachim H and Zieman, Susan J and Siscovick, David S and Gottdiener, John S and Rosenberg, Michael A and Kronmal, Richard A and Heckbert, Susan R and Kizer, Jorge R} } @article {7140, title = {Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes.}, journal = {Circ Heart Fail}, volume = {9}, year = {2016}, month = {2016 Jun}, abstract = {

BACKGROUND: Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF).

METHODS AND RESULTS: Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95\% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95\% CI, 0.77-0.82 and external: 0.76; 95\% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95\% CI, 0.80-0.84) and validation samples (internal: 0.80; 95\% CI, 0.78-0.83 and external: 0.76; 95\% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison <=0.02).

CONCLUSIONS: We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.

}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.115.003116}, author = {Ho, Jennifer E and Enserro, Danielle and Brouwers, Frank P and Kizer, Jorge R and Shah, Sanjiv J and Psaty, Bruce M and Bartz, Traci M and Santhanakrishnan, Rajalakshmi and Lee, Douglas S and Chan, Cheeling and Liu, Kiang and Blaha, Michael J and Hillege, Hans L and van der Harst, Pim and van Gilst, Wiek H and Kop, Willem J and Gansevoort, Ron T and Vasan, Ramachandran S and Gardin, Julius M and Levy, Daniel and Gottdiener, John S and de Boer, Rudolf A and Larson, Martin G} } @article {6850, title = {Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {71}, year = {2016}, month = {2016 Mar}, pages = {370-7}, abstract = {

BACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse.

METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic.

RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models.

CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.

}, keywords = {Aged, Aging, Blood Glucose, Cardiovascular Diseases, Fasting, Female, Follow-Up Studies, Glucose, Glucose Tolerance Test, Health Surveys, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Survival Rate, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glv106}, author = {Brutsaert, Erika F and Shitole, Sanyog and Biggs, Mary Lou and Mukamal, Kenneth J and deBoer, Ian H and Thacker, Evan L and Barzilay, Joshua I and Djouss{\'e}, Luc and Ix, Joachim H and Smith, Nicholas L and Kaplan, Robert C and Siscovick, David S and Psaty, Bruce M and Kizer, Jorge R} } @article {7249, title = {Testosterone, Dihydrotestosterone, Sex Hormone Binding Globulin and Incident Diabetes among Older Men: the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, year = {2016}, month = {2016 Oct 12}, pages = {jc20162623}, abstract = {

CONTEXT: Although sex hormone binding globulin (SHBG) and testosterone (T) have been inversely associated with risk of diabetes, few studies have examined dihydrotestosterone (DHT), a more potent androgen than T, or older adults, whose glycemic pathophysiology differs from younger adults.

OBJECTIVE: To determine the associations of SHBG, T, and DHT with insulin resistance and incident diabetes in older adult men.

DESIGN: In a prospective cohort study, we evaluated baseline levels of SHBG, T, and DHT using liquid chromatography-tandem mass spectrometry among 852 men in the Cardiovascular Health Study free of diabetes and cardiovascular disease in 1994.

MAIN OUTCOME: Insulin resistance estimated by HOMA-IR and insulin sensitivity estimated by the Gutt index in 1996, and incident diabetes (n=112) ascertained over a mean follow-up of 9.8 years.

RESULTS: In linear regression models adjusted for demographics, alcohol consumption, current smoking, body-mass index, and other androgens, SHBG (HOMA-IR 0.30 units lower per doubling; 95\% confidence interval [CI], 0.08-0.52; p=0.01) and total DHT (HOMA-IR 0.18 units lower per doubling; 95\% CI 0.06-0.30; p=0.01), but not free T (p=0.33) were inversely associated with insulin resistance. In corresponding Cox proportional hazards models, total DHT was again inversely associated with risk of diabetes (adjusted hazard ratio per doubling 0.69; 95\% CI, 0.52-0.92; p=0.01), but SHBG (hazard ratio 1.09; 95\% CI, 0.74-1.59; p=0.66) and free T (hazard ratio 1.15; 95\% CI, 0.92-1.43; p=0.23) were not.

CONCLUSIONS: Among older men, higher levels of DHT are inversely associated with insulin resistance and risk of diabetes over the ensuing 10 years, while levels of T are not. Future studies are still needed to clarify the role of SHBG in risk of diabetes in this population.

}, issn = {1945-7197}, doi = {10.1210/jc.2016-2623}, author = {Joyce, Katherine E and Biggs, Mary L and Djouss{\'e}, Luc and Ix, Joachim H and Kizer, Jorge R and Siscovick, David S and Shores, Molly M and Matsumoto, Alvin M and Mukamal, Kenneth J} } @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 {7141, title = {Trans-ethnic Meta-analysis and Functional Annotation Illuminates the~Genetic Architecture of Fasting Glucose and Insulin.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {56-75}, abstract = {

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.006}, author = {Liu, Ching-Ti and Raghavan, Sridharan and Maruthur, Nisa and Kabagambe, Edmond Kato and Hong, Jaeyoung and Ng, Maggie C Y and Hivert, Marie-France and Lu, Yingchang and An, Ping and Bentley, Amy R and Drolet, Anne M and Gaulton, Kyle J and Guo, Xiuqing and Armstrong, Loren L and Irvin, Marguerite R and Li, Man and Lipovich, Leonard and Rybin, Denis V and Taylor, Kent D and Agyemang, Charles and Palmer, Nicholette D and Cade, Brian E and Chen, Wei-Min and Dauriz, Marco and Delaney, Joseph A C and Edwards, Todd L and Evans, Daniel S and Evans, Michele K and Lange, Leslie A and Leong, Aaron and Liu, Jingmin and Liu, Yongmei and Nayak, Uma and Patel, Sanjay R and Porneala, Bianca C and Rasmussen-Torvik, Laura J and Snijder, Marieke B and Stallings, Sarah C and Tanaka, Toshiko and Yanek, Lisa R and Zhao, Wei and Becker, Diane M and Bielak, Lawrence F and Biggs, Mary L and Bottinger, Erwin P and Bowden, Donald W and Chen, Guanjie and Correa, Adolfo and Couper, David J and Crawford, Dana C and Cushman, Mary and Eicher, John D and Fornage, Myriam and Franceschini, Nora and Fu, Yi-Ping and Goodarzi, Mark O and Gottesman, Omri and Hara, Kazuo and Harris, Tamara B and Jensen, Richard A and Johnson, Andrew D and Jhun, Min A and Karter, Andrew J and Keller, Margaux F and Kho, Abel N and Kizer, Jorge R and Krauss, Ronald M and Langefeld, Carl D and Li, Xiaohui and Liang, Jingling and Liu, Simin and Lowe, William L and Mosley, Thomas H and North, Kari E and Pacheco, Jennifer A and Peyser, Patricia A and Patrick, Alan L and Rice, Kenneth M and Selvin, Elizabeth and Sims, Mario and Smith, Jennifer A and Tajuddin, Salman M and Vaidya, Dhananjay and Wren, Mary P and Yao, Jie and Zhu, Xiaofeng and Ziegler, Julie T and Zmuda, Joseph M and Zonderman, Alan B and Zwinderman, Aeilko H and Adeyemo, Adebowale and Boerwinkle, Eric and Ferrucci, Luigi and Hayes, M Geoffrey and Kardia, Sharon L R and Miljkovic, Iva and Pankow, James S and Rotimi, Charles N and Sale, Mich{\`e}le M and Wagenknecht, Lynne E and Arnett, Donna K and Chen, Yii-Der Ida and Nalls, Michael A and Province, Michael A and Kao, W H Linda and Siscovick, David S and Psaty, Bruce M and Wilson, James G and Loos, Ruth J F and Dupuis, Jos{\'e}e and Rich, Stephen S and Florez, Jose C and Rotter, Jerome I and Morris, Andrew P and Meigs, James B} } @article {7436, title = {Addition of 24-Hour Heart Rate Variability Parameters to the Cardiovascular Health Study Stroke Risk Score and Prediction of Incident Stroke: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Jul 21}, abstract = {

BACKGROUND: Heart rate variability (HRV) characterizes cardiac autonomic functioning. The association of HRV with stroke is uncertain. We examined whether 24-hour HRV added predictive value to the Cardiovascular Health Study clinical stroke risk score (CHS-SCORE), previously developed at the baseline examination.

METHODS AND RESULTS: N=884 stroke-free CHS participants (age 75.3{\textpm}4.6), with 24-hour Holters adequate for HRV analysis at the 1994-1995 examination, had 68 strokes over <=8~year follow-up (median 7.3 [interquartile range 7.1-7.6] years). The value of adding HRV to the CHS-SCORE was assessed with stepwise Cox regression analysis. The CHS-SCORE predicted incident stroke (HR=1.06 per unit increment, P=0.005). Two HRV parameters, decreased coefficient of variance of NN intervals (CV\%, P=0.031) and decreased power law slope (SLOPE, P=0.033) also entered the model, but these did not significantly improve the c-statistic (P=0.47). In a secondary analysis, dichotomization of CV\% (LOWCV\% <=12.8\%) was found to maximally stratify higher-risk participants after adjustment for CHS-SCORE. Similarly, dichotomizing SLOPE (LOWSLOPE <-1.4) maximally stratified higher-risk participants. When these HRV categories were combined (eg, HIGHCV\% with HIGHSLOPE), the c-statistic for the model with the CHS-SCORE and combined HRV categories was 0.68, significantly higher than 0.61 for the CHS-SCORE alone (P=0.02).

CONCLUSIONS: In this sample of older adults, 2 HRV parameters, CV\% and power law slope, emerged as significantly associated with incident stroke when added to a validated clinical risk score. After each parameter was dichotomized based on its optimal cut point in this sample, their composite significantly improved prediction of incident stroke during <=8-year follow-up. These findings will require validation in separate, larger cohorts.

}, issn = {2047-9980}, doi = {10.1161/JAHA.116.004305}, author = {Bodapati, Rohan K and Kizer, Jorge R and Kop, Willem J and Kamel, Hooman and Stein, Phyllis K} } @article {7344, title = {Bone Mineral Density and Risk of Heart Failure in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {6}, year = {2017}, month = {2017 Mar 13}, abstract = {

BACKGROUND: Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density (BMD) and heart failure (HF) risk remains insufficiently studied.

METHODS AND RESULTS: We investigated whether BMD measured by dual-energy x-ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55\% women) developed HF during the median follow-up of 10.5~years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF, with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95\% CI, 1.01-1.26] per 0.1~g/cm(2) decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95\% CI, 0.59-0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95\% CI, 1.39-5.74]) compared with normal BMD.

CONCLUSIONS: Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.

}, issn = {2047-9980}, doi = {10.1161/JAHA.116.004344}, author = {Fohtung, Raymond B and Brown, David L and Koh, William J H and Bartz, Traci M and Carbone, Laura D and Civitelli, Roberto and Stein, Phyllis K and Chaves, Paulo H M and Kestenbaum, Bryan R and Kizer, Jorge R} } @article {7328, title = {Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {Hum Mol Genet}, year = {2017}, month = {2017 Apr 03}, abstract = {

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

}, issn = {1460-2083}, doi = {10.1093/hmg/ddx091}, author = {Jensen, Majken K and Jensen, Richard A and Mukamal, Kenneth J and Guo, Xiuqing and Yao, Jie and Sun, Qi and Cornelis, Marilyn and Liu, Yongmei and Chen, Ming-Huei and Kizer, Jorge R and Djouss{\'e}, Luc and Siscovick, David S and Psaty, Bruce M and Zmuda, Joseph M and Rotter, Jerome I and Garcia, Melissa and Harris, Tamara and Chen, Ida and Goodarzi, Mark O and Nalls, Michael A and Keller, Margaux and Arnold, Alice M and Newman, Anne and Hoogeeven, Ron C and Rexrode, Kathryn M and Rimm, Eric B and Hu, Frank B and Vasan, Ramachandran S and Katz, Ronit and Pankow, James S and Ix, Joachim H} } @article {7351, title = {Higher plasma transforming growth factor (TGF)-β is associated with kidney disease in older community dwelling adults.}, journal = {BMC Nephrol}, volume = {18}, year = {2017}, month = {2017 Mar 21}, pages = {98}, abstract = {

BACKGROUND: TGF-β is induced in the vasculature with aging suggesting that high plasma TGF-β levels may be a risk factor for chronic kidney disease (CKD) in older adults.

METHODS: We conducted a cross-sectional analysis of the association between plasma TGF-β levels and CKD including data for 1722 older adults who had participated in the 1996/97 visit of the Cardiovascular Health Study (CHS). Prevalent CKD was defined as eGFR < 60~mL/min/1.73~m(2) or urinary albumin/creatinine ratio (ACR) >=30~mg/g. We also evaluated whether baseline TGF-β levels predicted change in eGFR, cardiovascular (CV) events, or mortality in longitudinal analysis.

RESULTS: Plasma TGF-β levels were significantly and independently associated with lower eGFR in cross-sectional analysis. Doubling of TGF-β was significantly associated with lower eGFR (β estimate after adjusting for CV risk factors = -1.18, 95\% CI -2.03, -0.32). We observed no association with albuminuria. There was no association between baseline TGF-β and change in eGFR, but each doubling of TGF-β at baseline was associated with increased risk of a composite outcome of CV events and mortality, adjusted HR 1.10 (95\% C.I. 1.02- 1.20, p = 0.006).

CONCLUSION: In this large cohort of community-dwelling older individuals, high plasma TGF-β levels are modestly, but independently associated with lower eGFR but not with albuminuria in cross-sectional analysis. In addition, TGF-β levels are associated with increased risk of CV events and mortality. Further research is needed to determine the direction of association between plasma TGF-β and the risk of CKD and CKD-associated morbidities in older adults.

}, issn = {1471-2369}, doi = {10.1186/s12882-017-0509-6}, author = {Mehta, Tapan and B{\r u}zkov{\'a}, Petra and Kizer, Jorge R and Djouss{\'e}, Luc and Chonchol, Michel and Mukamal, Kenneth J and Shlipak, Michael and Ix, Joachim H and Jalal, Diana} } @article {7549, title = {Predictors and outcomes of heart failure with mid-range ejection fraction.}, journal = {Eur J Heart Fail}, year = {2017}, month = {2017 Dec 11}, abstract = {

AIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49\%], HFpEF (EF >=50\%), and HFrEF (EF <=40\%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P~<= 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P~<= 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95\% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95\% CI 1.20-1.90, P~= 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95\% CI 1.41-1.73, P~= 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P~= 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P~= 0.78).

CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

}, issn = {1879-0844}, doi = {10.1002/ejhf.1091}, author = {Bhambhani, Vijeta and Kizer, Jorge R and Lima, Jo{\~a}o A C and van der Harst, Pim and Bahrami, Hossein and Nayor, Matthew and de Filippi, Christopher R and Enserro, Danielle and Blaha, Michael J and Cushman, Mary and Wang, Thomas J and Gansevoort, Ron T and Fox, Caroline S and Gaggin, Hanna K and Kop, Willem J and Liu, Kiang and Vasan, Ramachandran S and Psaty, Bruce M and Lee, Douglas S and Brouwers, Frank P and Hillege, Hans L and Bartz, Traci M and Benjamin, Emelia J and Chan, Cheeling and Allison, Matthew and Gardin, Julius M and Januzzi, James L and Levy, Daniel and Herrington, David M and van Gilst, Wiek H and Bertoni, Alain G and Larson, Martin G and de Boer, Rudolf A and Gottdiener, John S and Shah, Sanjiv J and Ho, Jennifer E} } @article {7350, title = {Relation of the Myocardial Contraction Fraction, as Calculated from M-Mode Echocardiography, With Incident Heart Failure, Atherosclerotic Cardiovascular Disease and Mortality (Results from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {119}, year = {2017}, month = {2017 Mar 15}, pages = {923-928}, abstract = {

We evaluated the association between 2-dimensional (2D) echocardiography (echo)-determined myocardial contraction fraction (MCF) and adverse cardiovascular outcomes including incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and mortality. The MCF, the ratio of left ventricular (LV) stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that can distinguish pathologic from physiological hypertrophy. Using 2D echo-guided M-mode data from the~Cardiovascular Health Study, we calculated MCF in subjects with LV ejection fraction (EF) >=55\% and used Cox models to evaluate its association with incident HF, ASCVD, and all-cause mortality after adjusting for clinical and echo parameters. We assessed whether log2(SV) and log2(MV) were consistent with the expected 1:-1 ratio used in the definition of MCF. Among 2,147 participants (age 72 {\textpm} 5 years), average MCF was 59 {\textpm} 13\%. After controlling for clinical and echo variables, each 10\% absolute increment in MCF was associated with lower risk of HF (hazard ratio [HR] 0.88; 95\% confidence interval [CI] 0.82, 0.94), ASCVD (HR 0.90; 95\% CI 0.85, 0.95), and death (HR 0.93; 95\% CI 0.89, 0.97). Moreover, the MCF was still significantly associated with ASCVD and mortality, but not HF, after adjustment for percent-predicted LV mass. Significant departure from the 1:-1 ratio was not observed for ASCVD or death, but did occur for HF, driven by a stronger association for MV than SV. In conclusion, among older adults without CVD or low LV ejection fraction, 2D echo-guided M-mode-derived MCF was independently associated with lower risk of adverse cardiovascular outcomes, but this ratiometric index may not capture the full relation that is apparent when its components are modeled separately in the~case of HF.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2016.11.048}, author = {Maurer, Mathew S and Koh, William J H and Bartz, Traci M and Vullaganti, Sirish and Barasch, Eddy and Gardin, Julius M and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @article {7488, title = {Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study.}, journal = {Arch Osteoporos}, volume = {12}, year = {2017}, month = {2017 Dec}, pages = {52}, abstract = {

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found.

INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse.

METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression.

RESULTS: Mean (SD) age was 76.2 (4.8)~years; 58\% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0\%; AAC 45.1 and 46.7\%; MAC 42.8 and 39.5\%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD~=~1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant.

CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

}, issn = {1862-3514}, doi = {10.1007/s11657-017-0347-y}, author = {Massera, Daniele and Xu, Shuo and Bartz, Traci M and Bortnick, Anna E and Ix, Joachim H and Chonchol, Michel and Owens, David S and Barasch, Eddy and Gardin, Julius M and Gottdiener, John S and Robbins, John R and Siscovick, David S and Kizer, Jorge R} } @article {7336, title = {Sleep-disordered breathing is associated with higher carboxymethyllysine level in elderly women but not elderly men in the cardiovascular health study.}, journal = {Biomarkers}, volume = {22}, year = {2017}, month = {2017 May - Jun}, pages = {361-366}, abstract = {

CONTEXT: Carboxymethyl-lysine (CML) results from oxidative stress and has been linked to cardiovascular disease.

OBJECTIVE: The objective of this study is to investigate the association between sleep-disordered breathing (SDB) - a source of oxidative stress - and CML.

MATERIALS AND METHODS: About 1002 participants in the Cardiovascular Health Study (CHS) were studied.

RESULTS: Women with SDB had significantly higher CML concentration compared with those without SDB (OR = 1.63, 95\%CI = 1.03-2.58, p = 0.04). The association was not significant among men.

DISCUSSION: SDB was associated with CML concentration among elderly women but not men in the Cardiovascular Health Study.

CONCLUSION: Accumulation of CML may be an adverse health consequence of SDB.

}, issn = {1366-5804}, doi = {10.1080/1354750X.2016.1276966}, author = {Ahiawodzi, Peter D and Kerber, Richard A and Taylor, Kira C and Groves, Frank D and O{\textquoteright}Brien, Elizabeth and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and Tracy, Russell P and Newman, Anne B and Siscovick, David S and Robbins, John and Mukamal, Kenneth} } @article {7983, title = {Association of Alcohol Consumption After Development of Heart Failure With Survival Among Older Adults in the Cardiovascular Health Study.}, journal = {JAMA Netw Open}, volume = {1}, year = {2018}, month = {2018 Dec 07}, pages = {e186383}, abstract = {

Importance: More than 1 million older adults develop heart failure annually. The association of alcohol consumption with survival among these individuals after diagnosis is unknown.

Objective: To determine whether alcohol use is associated with increased survival among older adults with incident heart failure.

Design, Setting, and Participants: This prospective cohort study included 5888 community-dwelling adults aged 65 years or older who were recruited to participate in the Cardiovascular Health Study between June 12, 1989, and June 1993, from 4 US sites. Of the total participants, 393 individuals had a new diagnosis of heart failure within the first 9 years of follow-up through June 2013. The study analysis was performed between January 19, 2016, and September 22, 2016.

Exposures: Alcohol consumption was divided into 4 categories: abstainers (never drinkers), former drinkers, 7 or fewer alcoholic drinks per week, and more than 7 drinks per week.

Primary Outcomes and Measures: Participant survival after the diagnosis of incident heart failure.

Results: Among the 393 adults diagnosed with incident heart failure, 213 (54.2\%) were female, 339 (86.3\%) were white, and the mean (SD) age was 78.7 (6.0) years. Alcohol consumption after diagnosis was reported in 129 (32.8\%) of the participants. Across alcohol consumption categories of long-term abstainers, former drinkers, consumers of 1-7 drinks weekly and consumers of more than 7 drinks weekly, the percentage of men (32.1\%, 49.0\%, 58.0\%, and 82.4\%, respectively; P < .001 for trend), white individuals (78.0\%, 92.7\%, 92.0\%, and 94.1\%, respectively, P <. 001 for trend), and high-income participants (22.0\%, 43.8\%, 47.3\%, and 64.7\%, respectively; P < .001 for trend) increased with increasing alcohol consumption. Across the 4 categories, participants who consumed more alcohol had more years of education (mean, 12 years [interquartile range (IQR), 8.0-10.0 years], 12 years [IQR, 11.0-14.0 years], 13 years [IQR, 12.0-15.0 years], and 13 years [IQR, 12.0-14.0 years]; P < .001 for trend). Diabetes was less common across the alcohol consumption categories (32.1\%, 26.0\%, 22.3\%, and 5.9\%, respectively; P = .01 for trend). Across alcohol consumption categories, there were fewer never smokers (58.3\%, 44.8\%, 35.7\%, and 29.4\%, respectively; P < .001 for trend) and more former smokers (34.5\%, 38.5\%, 50.0\%, and 52.9\%, respectively; P = .006 for trend). After controlling for other factors, consumption of 7 or fewer alcoholic drinks per week was associated with additional mean survival of 383 days (95\% CI, 17-748 days; P = .04) compared with abstinence from alcohol. Although the robustness was limited by the small number of individuals who consumed more than 7 drinks per week, a significant inverted U-shaped association between alcohol consumption and survival was observed. Multivariable model estimates of mean time from heart failure diagnosis to death were 2640 days (95\% CI, 1967-3313 days) for never drinkers, 3046 days (95\% CI, 2372-3719 days) for consumers of 0 to 7 drinks per week, and 2806 (95\% CI, 1879-3734 days) for consumers of more than 7 drinks per week (P = .02). Consumption of 10 drinks per week was associated with the longest survival, a mean of 3381 days (95\% CI, 2806-3956 days) after heart failure diagnosis.

Conclusions and Relevance: These findings suggest that limited alcohol consumption among older adults with incident heart failure is associated with survival benefit compared with long-term abstinence. These findings suggest that older adults who develop heart failure may not need to abstain from moderate levels of alcohol consumption.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2018.6383}, author = {Sadhu, Justin S and Novak, Eric and Mukamal, Kenneth J and Kizer, Jorge R and Psaty, Bruce M and Stein, Phyllis K and Brown, David L} } @article {7671, title = {Association of biomarker and physiologic indices with mortality in older adults: Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2018}, month = {2018 Apr 12}, abstract = {

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

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

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

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

}, issn = {1758-535X}, doi = {10.1093/gerona/gly075}, author = {Sanders, Jason L and Arnold, Alice M and Boudreau, Robert M and Hirsch, Calvin H and Kizer, Jorge R and Kaplan, Robert C and Cappola, Anne R and Cushman, Mary and Jacob, Mini E and Kritchevsky, Stephen B and Newman, Anne B} } @article {7603, title = {Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.}, journal = {JAMA Cardiol}, year = {2018}, month = {2018 Jan 10}, abstract = {

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.

Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.

Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.

Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.

Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF.

Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95\% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95\% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95\% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95\% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95\% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95\% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95\% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95\% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95\% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95\% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95\% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.

Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2017.4987}, author = {de Boer, Rudolf A and Nayor, Matthew and deFilippi, Christopher R and Enserro, Danielle and Bhambhani, Vijeta and Kizer, Jorge R and Blaha, Michael J and Brouwers, Frank P and Cushman, Mary and Lima, Jo{\~a}o A C and Bahrami, Hossein and van der Harst, Pim and Wang, Thomas J and Gansevoort, Ron T and Fox, Caroline S and Gaggin, Hanna K and Kop, Willem J and Liu, Kiang and Vasan, Ramachandran S and Psaty, Bruce M and Lee, Douglas S and Hillege, Hans L and Bartz, Traci M and Benjamin, Emelia J and Chan, Cheeling and Allison, Matthew and Gardin, Julius M and Januzzi, James L and Shah, Sanjiv J and Levy, Daniel and Herrington, David M and Larson, Martin G and van Gilst, Wiek H and Gottdiener, John S and Bertoni, Alain G and Ho, Jennifer E} } @article {7678, title = {Association of lipoprotein-associated phospholipase A and risk of incident atrial fibrillation: Findings from 3 cohorts.}, journal = {Am Heart J}, volume = {197}, year = {2018}, month = {2018 Mar}, pages = {62-69}, abstract = {

BACKGROUND: Multiple prospective studies have established an association between inflammation and higher risk of atrial fibrillation (AF), but the association between lipoprotein-associated phospholipase A (Lp-PLA) mass and activity and incident AF has not been extensively evaluated.

METHODS: Using data from 10,794 Atherosclerosis Risk In Communities (ARIC) study participants aged 53-75 years, 5,181 Cardiovascular Health Study (CHS) participants aged 65 to 100 years, and 5,425 Multi-Ethnic Study of Atherosclerosis (MESA) participants aged 45-84 years, we investigated the association between baseline Lp-PLA levels and the risk of developing AF. Incident AF was identified in each cohort by follow-up visit electrocardiograms, hospital discharge coding of AF, or Medicare claims data.

RESULTS: Over a mean of 13.1, 11.5, and 10.0 years of follow-up, 1,439 (13\%), 2,084 (40\%), and 615 (11\%) incident AF events occurred in ARIC, CHS, and MESA, respectively. In adjusted analyses, each SD increment in Lp-PLA activity was associated with incident AF in both ARIC (hazard ratio [HR] 1.13, 95\% CI 1.06-1.20) and MESA (HR 1.24, 95\% CI 1.05-1.46). Each SD increment in Lp-PLA mass was also associated with incident AF in MESA (HR 1.25, 95\% CI 1.11-1.41). No significant associations were observed among CHS participants.

CONCLUSIONS: Although higher Lp-PLA mass and activity were associated with development of AF in ARIC and MESA, this relationship was not observed in CHS, a cohort of older individuals.

}, issn = {1097-6744}, doi = {10.1016/j.ahj.2017.11.010}, author = {Garg, Parveen K and Bartz, Traci M and Norby, Faye L and Jorgensen, Neal W and McClelland, Robyn L and Ballantyne, Christie M and Chen, Lin Y and Gottdiener, John S and Greenland, Philip and Hoogeveen, Ron and Jenny, Nancy S and Kizer, Jorge R and Rosenson, Robert S and Soliman, Elsayed Z and Cushman, Mary and Alonso, Alvaro and Heckbert, Susan R} } @article {7812, title = {The Association of Obesity and Cardiometabolic Traits With Incident~HFpEF and HFrEF.}, journal = {JACC Heart Fail}, volume = {6}, year = {2018}, month = {2018 Aug}, pages = {701-709}, abstract = {

OBJECTIVES: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately.

BACKGROUND: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.

METHODS: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction >=50\% vs.~<50\%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models.

RESULTS: The mean age was 60 {\textpm} 13 years, and 53\% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95\% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95\% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95\% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95\% CI: 0.88 to 1.11; p~< 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF~= 0.01) when compared with men (p~= 0.34).

CONCLUSIONS: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among~women and may underlie sex differences in HF subtypes.

}, issn = {2213-1787}, doi = {10.1016/j.jchf.2018.05.018}, author = {Savji, Nazir and Meijers, Wouter C and Bartz, Traci M and Bhambhani, Vijeta and Cushman, Mary and Nayor, Matthew and Kizer, Jorge R and Sarma, Amy and Blaha, Michael J and Gansevoort, Ron T and Gardin, Julius M and Hillege, Hans L and Ji, Fei and Kop, Willem J and Lau, Emily S and Lee, Douglas S and Sadreyev, Ruslan and van Gilst, Wiek H and Wang, Thomas J and Zanni, Markella V and Vasan, Ramachandran S and Allen, Norrina B and Psaty, Bruce M and van der Harst, Pim and Levy, Daniel and Larson, Martin and Shah, Sanjiv J and de Boer, Rudolf A and Gottdiener, John S and Ho, Jennifer E} } @article {7804, title = {Biochemical Markers of Bone Turnover and Risk of Incident Diabetes in Older Women: The Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {41}, year = {2018}, month = {2018 09}, pages = {1901-1908}, abstract = {

OBJECTIVE: To investigate the relationship of osteocalcin (OC), a marker of bone formation, and C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone resorption, with incident diabetes in older women.

RESEARCH DESIGN AND METHODS: The analysis included 1,455 female participants from the population-based Cardiovascular Health Study (CHS) (mean [SD] age 74.6 [5.0] years). The cross-sectional association of serum total OC and CTX levels with insulin resistance (HOMA-IR) was examined using multiple linear regression. The longitudinal association of both markers with incident diabetes, defined by follow-up glucose measurements, medications, and ICD-9 codes, was examined using multivariable Cox proportional hazards models.

RESULTS: OC and CTX were strongly correlated ( = 0.80). In cross-sectional analyses, significant or near-significant inverse associations with HOMA-IR were observed for continuous levels of OC (β = -0.12 per SD increment; = 0.004) and CTX (β = -0.08 per SD; = 0.051) after full adjustment for demographic, lifestyle, and clinical covariates. During a median follow-up of 11.5 years, 196 cases of incident diabetes occurred. After full adjustment, both biomarkers exhibited inverse associations with incident diabetes (OC: hazard ratio 0.85 per SD [95\% CI 0.71-1.02; = 0.075]; CTX: 0.82 per SD [0.69-0.98; = 0.031]), associations that were comparable in magnitude and approached or achieved statistical significance.

CONCLUSIONS: In late postmenopausal women, lower OC and CTX levels were associated with similarly increased risks of insulin resistance at baseline and incident diabetes over long-term follow-up. Further research to delineate the mechanisms linking abnormal bone homeostasis and energy metabolism could uncover new approaches for the prevention of these age-related disorders.

}, issn = {1935-5548}, doi = {10.2337/dc18-0849}, author = {Massera, Daniele and Biggs, Mary L and Walker, Marcella D and Mukamal, Kenneth J and Ix, Joachim H and Djouss{\'e}, Luc and Valderr{\'a}bano, Rodrigo J and Siscovick, David S and Tracy, Russell P and Xue, XiaoNan and Kizer, Jorge R} } @article {8539, title = {Metabolic Clusters and Outcomes in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {66}, year = {2018}, month = {2018 02}, pages = {289-296}, abstract = {

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

DESIGN: Population-based prospective cohort study.

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

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

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

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

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

}, keywords = {Aged, Aged, 80 and over, Blood Glucose, C-Reactive Protein, Cardiovascular Diseases, Diabetes Mellitus, Female, Glomerular Filtration Rate, Humans, Incidence, Insulin, Longitudinal Studies, Male, Prospective Studies, Risk Factors, United States}, issn = {1532-5415}, doi = {10.1111/jgs.15205}, author = {Mukamal, Kenneth J and Siscovick, David S and de Boer, Ian H and Ix, Joachim H and Kizer, Jorge R and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Tracy, Russell P and Boyko, Edward J and Kahn, Steven E and Arnold, Alice M} } @article {7814, title = {Temporal Trends in the Incidence of~and~Mortality Associated With Heart~Failure With Preserved and Reduced Ejection Fraction.}, journal = {JACC Heart Fail}, volume = {6}, year = {2018}, month = {2018 Aug}, pages = {678-685}, abstract = {

OBJECTIVES: This study aimed to determine temporal trends in the incidence of and mortality associated with heart failure (HF) and its subtypes (heart failure with reduced ejection fraction [HFrEF] and heart rate with preserved ejection fraction [HFpEF]) in the community.

BACKGROUND: Major shifts in cardiovascular disease risk factor prevalence and advances in therapies may have influenced HF incidence and mortality.

METHODS: In the FHS (Framingham Heart Study) and CHS (Cardiovascular Health Study), for participants who were~>=60 years of age and free of HF (n~= 15,217; 60\% women; 2,524 incident HF cases; 115,703 person-years of follow-up), we estimated adjusted incidence rate ratios of HF, HFrEF, and HFpEF from 1990 to 1999 and 2000 to 2009. We compared the cumulative incidence of and mortality associated with HFrEF versus HFpEF within and between decades.

RESULTS: Across the 2 decades, HF incidence rate ratio was similar (p~= 0.13). The incidence rate ratio of HFrEF declined (p~= 0.0029), whereas HFpEF increased (p~< 0.001). Although HFrEF incidence declined more in men than in women, men had a higher incidence of HFrEF than women in each decade (p~< 0.001). The incidence of HFpEF significantly increased over time in both men and women (p~< 0.001 and p~= 0.02, respectively). During follow-up after HF, 1,701 individuals died (67.4\%; HFrEF, n~= 557 [33\%]; HFpEF, n~= 474 [29\%]). There were no significant differences in mortality~rates (overall, cardiovascular disease, and noncardiovascular disease) across decades within HF subtypes or between HFrEF and HFpEF within decade.

CONCLUSIONS: In several U.S. community-based samples from 1990 to 2009, we observed divergent trends of decreasing HFrEF and increasing HFpEF incidence, with stable overall HF incidence and high risk for mortality. Our~findings highlight the need to elucidate factors contributing to these observations.

}, issn = {2213-1787}, doi = {10.1016/j.jchf.2018.03.006}, author = {Tsao, Connie W and Lyass, Asya and Enserro, Danielle and Larson, Martin G and Ho, Jennifer E and Kizer, Jorge R and Gottdiener, John S and Psaty, Bruce M and Vasan, Ramachandran S} } @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 {8486, title = {Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.}, journal = {JCI Insight}, volume = {5}, year = {2020}, month = {2020 Oct 02}, abstract = {

BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear.

METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF.

RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4\%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95\% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain.

CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.

FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH{\textquoteright}s National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

}, issn = {2379-3708}, doi = {10.1172/jci.insight.141656}, author = {Patel, Ravi B and Delaney, Joseph A and Hu, Mo and Patel, Harnish and Cheng, Jeanette and Gottdiener, John and Kizer, Jorge R and Marcus, Gregory M and Turakhia, Mintu P and Deo, Rajat and Heckbert, Susan R and Psaty, Bruce M and Shah, Sanjiv J} } @article {8369, title = {Fatty Acid Binding Protein-4 and Risk of Cardiovascular Disease: The Cardiovascular Health Study.}, journal = {J Am Heart Assoc}, volume = {9}, year = {2020}, month = {2020 Apr 07}, pages = {e014070}, abstract = {

Background FABP-4 (fatty acid binding protein-4) is a lipid chaperone in adipocytes and has been associated with prognosis in selected clinical populations. We investigated the associations between circulating FABP-4, risk of incident cardiovascular disease (CVD), and risk of CVD mortality among older adults with and without established CVD. Methods and Results In the Cardiovascular Health Study, we measured FABP4 levels in stored specimens from the 1992-993 visit and followed participants for incident CVD if they were free of prevalent CVD at baseline and for CVD mortality through June 2015. We used Cox regression to estimate hazard ratios for incident CVD and CVD mortality per doubling in serum FABP-4 adjusted for age, sex, race, field center, waist circumference, blood pressure, lipids, fasting glucose, and C-reactive protein. Among 4026 participants free of CVD and 681 with prevalent CVD, we documented 1878 cases of incident CVD and 331 CVD deaths, respectively. In adjusted analyses, FABP-4 was modestly associated with risk of incident CVD (mean, 34.24; SD, 18.90; HR, 1.10 per doubling in FABP-4, 95\% CI, 1.00-1.21). In contrast, FABP-4 was more clearly associated with risk of CVD mortality among participants without (HR hazard ratio 1.24, 95\% CI, 1.10-1.40) or with prevalent CVD (HR hazard ratio 1.57, 95\% CI, 1.24-1.98). These associations were not significantly modified by sex, age, and waist circumference. Conclusions Serum FABP-4 is modestly associated with risk of incident CVD even after adjustment for standard risk factors, but more strongly associated with CVD mortality among older adults with and without established CVD.

}, issn = {2047-9980}, doi = {10.1161/JAHA.119.014070}, author = {Egbuche, Obiora and Biggs, Mary L and Ix, Joachim H and Kizer, Jorge R and Lyles, Mary F and Siscovick, David S and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {8491, title = {Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.}, journal = {Diabetes}, year = {2020}, month = {2020 Sep 11}, abstract = {

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

}, issn = {1939-327X}, doi = {10.2337/db20-0070}, author = {Yaghootkar, Hanieh and Zhang, Yiying and Spracklen, Cassandra N and Karaderi, Tugce and Huang, Lam Opal and Bradfield, Jonathan and Schurmann, Claudia and Fine, Rebecca S and Preuss, Michael H and Kutalik, Zolt{\'a}n and Wittemans, Laura Bl and Lu, Yingchang and Metz, Sophia and Willems, Sara M and Li-Gao, Ruifang and Grarup, Niels and Wang, Shuai and Molnos, Sophie and Sandoval-Z{\'a}rate, Am{\'e}rica A and Nalls, Mike A and Lange, Leslie A and Haesser, Jeffrey and Guo, Xiuqing and Lyytik{\"a}inen, Leo-Pekka and Feitosa, Mary F and Sitlani, Colleen M and Venturini, Cristina and Mahajan, Anubha and Kacprowski, Tim and Wang, Carol A and Chasman, Daniel I and Amin, Najaf and Broer, Linda and Robertson, Neil and Young, Kristin L and Allison, Matthew and Auer, Paul L and Bl{\"u}her, Matthias and Borja, Judith B and Bork-Jensen, Jette and Carrasquilla, Germ{\'a}n D and Christofidou, Paraskevi and Demirkan, Ayse and Doege, Claudia A and Garcia, Melissa E and Graff, Mariaelisa and Guo, Kaiying and Hakonarson, Hakon and Hong, Jaeyoung and Ida Chen, Yii-Der and Jackson, Rebecca and Jakupovi{\'c}, Hermina and Jousilahti, Pekka and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Kizer, Jorge R and Kriebel, Jennifer and LeDuc, Charles A and Li, Jin and Lind, Lars and Luan, Jian{\textquoteright}an and Mackey, David and Mangino, Massimo and M{\"a}nnist{\"o}, Satu and Martin Carli, Jayne F and Medina-G{\'o}mez, Carolina and Mook-Kanamori, Dennis O and Morris, Andrew P and de Mutsert, Ren{\'e}e and Nauck, Matthias and Nedeljkovic, Ivana and Pennell, Craig E and Pradhan, Arund D and Psaty, Bruce M and Raitakari, Olli T and Scott, Robert A and Skaaby, Tea and Strauch, Konstantin and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Wu, Ying and Yao, Jie and Walker, Mark and North, Kari E and Kovacs, Peter and Ikram, M Arfan and van Duijn, Cornelia M and Ridker, Paul M and Lye, Stephen and Homuth, Georg and Ingelsson, Erik and Spector, Tim D and McKnight, Barbara and Province, Michael A and Lehtim{\"a}ki, Terho and Adair, Linda S and Rotter, Jerome I and Reiner, Alexander P and Wilson, James G and Harris, Tamara B and Ripatti, Samuli and Grallert, Harald and Meigs, James B and Salomaa, Veikko and Hansen, Torben and Willems van Dijk, Ko and Wareham, Nicholas J and Grant, Struan Fa and Langenberg, Claudia and Frayling, Timothy M and Lindgren, Cecilia M and Mohlke, Karen L and Leibel, Rudolph L and Loos, Ruth Jf and Kilpel{\"a}inen, Tuomas O} } @article {8476, title = {Non-Esterified Fatty Acids and Hospitalizations among Older Adults: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2020}, month = {2020 Sep 10}, abstract = {

BACKGROUND: We sought to determine associations between total serum concentrations of non-esterified fatty acids (NEFAs) and incident total and cause-specific hospitalizations in a community-living cohort of elders.

METHODS: We included 4715 participants in the Cardiovascular Health Study who had fasting total serum NEFA measured at the 1992/93 clinic visit and were followed for a median of 12 years. We identified all inpatient admissions requiring at least an overnight hospitalization and used primary diagnostic codes to categorize cause-specific hospitalizations. We used Cox proportional hazards regression models to determine associations with time-to-first hospitalization and Poisson regression for the rate ratios (RR) of hospitalizations and days hospitalized.

RESULTS: We identified 21339 hospitalizations during follow-up. In fully adjusted models, higher total NEFAs were significantly associated with higher risk of incident hospitalization (Hazard Ratio (HR) per SD [0.2 mEq/L]=1.07, 95\%CI=1.03-1.10, P\&0.001), number of hospitalizations (RR per SD=1.04, 95\%CI=1.01-1.07, P=0.01), and total number of days hospitalized (RR per SD=1.06, 95\%CI=1.01-1.10, P=0.01). Among hospitalization subtypes, higher NEFA was associated with higher likelihood of mental, neurologic, respiratory, and musculoskeletal causes of hospitalization. Among specific causes of hospitalization, higher NEFA was associated with diabetes, pneumonia, and gastrointestinal hemorrhage.

CONCLUSIONS: Higher fasting total serum NEFAs are associated with a broad array of causes of hospitalization among older adults. While some of these were expected, our results illustrate a possible utility of NEFAs as biomarkers for risk of hospitalization, and total days hospitalized, in older adults. Further research is needed to determine whether interventions based on NEFAs might be feasible.

}, issn = {1758-535X}, doi = {10.1093/gerona/glaa228}, author = {Ahiawodzi, Peter D and B{\r u}zkov{\'a}, Petra and Djouss{\'e}, Luc and Ix, Joachim H and Kizer, Jorge R and Mukamal, Kenneth J} } @article {8477, title = {Non-Esterified Fatty Acids and Risks of Frailty, Disability, and Mobility Limitation in Older Adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, year = {2020}, month = {2020 Sep 22}, abstract = {

BACKGROUND/OBJECTIVES: Non-esterified fatty acids (NEFAs) play central roles in the relationship between adiposity and glucose metabolism, and they have been implicated in the pathogenesis of cardiovascular disease, but few studies have assessed their effects on complex geriatric syndromes like frailty that cross multiple organ systems. We sought to determine the relationships between NEFAs and incident frailty, disability, and mobility limitation in a population-based cohort of older persons.

METHODS: We analyzed 4,710 Cardiovascular Health Study (CHS) participants who underwent measurement of circulating total fasting NEFAs in 1992-1993 and were assessed for frailty in 1996-1997 and for disability and mobility limitation annually. We used ordinal logistic regression to model incident frailty, linear regression to model components of frailty, and Cox regression to model disability and mobility limitation in relation to baseline NEFAs. To ensure proportional hazards, we truncated follow-up at 9 years for disability and 6.5 years for mobility limitation.

RESULTS: A total of 42 participants became frail and 510 became pre-frail over a 4-year period, and we documented 1,720 cases of disability and 1,225 cases of mobility limitation during follow-up. NEFAs were positively associated in a dose-dependent manner with higher risks of incident frailty, disability, and mobility limitation. The adjusted odds ratios for frailty were 1.37 (95\% confidence interval [CI] = 1.01-1.86; P = .04) across extreme tertiles and 1.17 (95\% CI = 1.03-1.33; P = .01) per standard deviation increment. The corresponding hazard ratios for incident disability were 1.14 (95\% CI = 1.01-1.30; P = .04) and 1.11 (95\% CI = 1.06-1.17; P < .0001); those for incident mobility limitation were 1.23 (95\% CI = 1.06-1.43; P = .006) and 1.15 (95\% CI = 1.08-1.22; P < .0001). Results were largely consistent among both men and women. Among individual components of frailty, NEFAs were significantly associated with self-reported exhaustion (β = .07; standard error = .03; P = .02).

CONCLUSION: Circulating NEFAs are significantly associated with frailty, disability, and mobility limitation among older adults. These results highlight the broad spectrum of adverse health issues associated with NEFA in older adults.

}, issn = {1532-5415}, doi = {10.1111/jgs.16793}, author = {Ahiawodzi, Peter and Djouss{\'e}, Luc and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Arnold, Alice and Newman, Anne and Mukamal, Kenneth J} } @article {8478, title = {Non-esterified fatty acids and telomere length in older adults: The Cardiovascular Health Study.}, journal = {Metabol Open}, volume = {8}, year = {2020}, month = {2020 Dec}, pages = {100058}, abstract = {

Background: Telomeres shorten as organisms age, placing limits on cell proliferation and serving as a marker of biological aging. Non-esterified fatty acids (NEFAs) are a key mediator of age-related metabolic abnormalities. We aimed to determine if NEFAs are associated with telomere length in community-living older adults.

Material and methods: We cross-sectionally studied 1648 participants of the Cardiovascular Health Study (CHS) who underwent concomitant telomere length measurement from a sample of 4715 participants who underwent measurement of circulating total fasting NEFAs in stored specimens from their 1992-3 clinic visit. We used linear regression and inverse probability weighting to model telomere length as a function of NEFAs with adjustment for age, gender, race, clinic, BMI, marital status, smoking status, alcohol intake, diabetes status, years of education, hypertension status, prevalent cardiovascular disease, C-reactive protein, total adiponectin, albumin, fetuin-A, fasting insulin, eGFR, total cholesterol, HDL-cholesterol, triglycerides, and general health status.

Results: Higher NEFAs were significantly associated with shorter telomere length, after adjusting for age, gender, race, and clinic site (β~=~-0.034; SE~=~0.015; ~=~0.02). Estimates remained similar in fully adjusted models where each SD of NEFA increment was associated with 0.042 kilobase (kb) pairs shorter telomere length (standard error~=~0.016; ~=~0.007); for comparison the coefficient for a single year of age in the same model was~-0.017. These results were similar in strata of sex, and waist circumference although they tended to be strongest among participants in the youngest tertile of age (β~=~-0.079; SE~=~0.029; P~=~0.01).

Conclusions: In this population-based cohort of community-living elders, we observed a significant inverse association between NEFAs and telomere length. If confirmed, NEFAs may represent a promising target for interventions to slow biological aging.

}, issn = {2589-9368}, doi = {10.1016/j.metop.2020.100058}, author = {Ahiawodzi, Peter and Fitzpatrick, Annette L and Djouss{\'e}, Luc and Ix, Joachim H and Kizer, Jorge R and Mukamal, Kenneth J} } @article {8482, title = {Relation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients >= 65 Years of Age.}, journal = {Am J Cardiol}, year = {2020}, month = {2020 Sep 16}, abstract = {

High sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β-0.06, p = 0.020), sST2 (β -0.05, p = 0.024) and NT-proBNP (β -0.06, p = 0.007). "High" levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β -0.08, p = 0.003) and NT-proBNP (β-0.18, p <0.0001). High hscTnT (>13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons >= 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2020.09.013}, author = {Gottdiener, John S and Seliger, Stephen and DeFilippi, Christopher and Christenson, Robert and Baldridge, Abigail S and Kizer, Jorge R and Psaty, Bruce M and Shah, Sanjiv J} } @article {8488, title = {Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {76}, year = {2020}, month = {2020 Sep 22}, pages = {1455-1465}, abstract = {

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

RESULTS: Among 22,756 participants (mean age 60 {\textpm} 13 years, 53\% women), HF occurred in 2,095 participants (47\% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p~<~0.001), and the combined clinical model had good discrimination in men (C-statistic~=~0.80) and in women (C-statistic~=~0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic~=~0.006; likelihood ratio chi-square~=~146; p~<~0.001), and after adding cardiac troponins in women (ΔC-statistic~=~0.003; likelihood ratio chi-square~=~73; p~<~0.001).

CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in~a~clinical HF risk prediction model is limited in both sexes.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.07.044}, author = {Suthahar, Navin and Lau, Emily S and Blaha, Michael J and Paniagua, Samantha M and Larson, Martin G and Psaty, Bruce M and Benjamin, Emelia J and Allison, Matthew A and Bartz, Traci M and Januzzi, James L and Levy, Daniel and Meems, Laura M G and Bakker, Stephan J L and Lima, Jo{\~a}o A C and Cushman, Mary and Lee, Douglas S and Wang, Thomas J and deFilippi, Christopher R and Herrington, David M and Nayor, Matthew and Vasan, Ramachandran S and Gardin, Julius M and Kizer, Jorge R and Bertoni, Alain G and Allen, Norrina B and Gansevoort, Ron T and Shah, Sanjiv J and Gottdiener, John S and Ho, Jennifer E and de Boer, Rudolf A} } @article {8376, title = {Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults.}, journal = {J Card Fail}, volume = {26}, year = {2020}, month = {2020 May}, pages = {410-419}, abstract = {

BACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.

METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as HF with preserved ejection fraction [HFpEF] and 419 as HF with reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (hazard ratio [HR]: 1.56 per doubling, 95\% confidence interval [CI]: 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling: 1.10, 95\% CI: 1.06-1.15), IL-6 (HR: 1.18, 95\% CI: 1.10-1.25), and WBC (HR: 1.24, 95\% CI: 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR: 1.50, 95\% CI: 1.07-2.10) but not HFrEF (HR: 0.99, 95\% CI: 0.67-1.49).

CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.

}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2020.03.003}, author = {Al-Kindi, Sadeer G and B{\r u}zkov{\'a}, Petra and Shitole, Sanyog G and Reiner, Alex P and Garg, Parveen K and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @article {8833, title = {Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.}, journal = {Heart}, year = {2021}, month = {2021 Jul 13}, abstract = {

OBJECTIVES: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults.

METHODS: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years.

RESULTS: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95\% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95\% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95\% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations.

CONCLUSION: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319296}, author = {Massera, Daniele and Hu, Mo and Delaney, Joseph A and Bartz, Traci M and Bach, Megan E and Dvorak, Stephen J and deFilippi, Christopher R and Psaty, Bruce M and Gottdiener, John S and Kizer, Jorge R and Shah, Sanjiv J} } @article {8707, title = {Associations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort.}, journal = {J Am Heart Assoc}, volume = {10}, year = {2021}, month = {2021 Mar 16}, pages = {e019135}, abstract = {

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

}, issn = {2047-9980}, doi = {10.1161/JAHA.120.019135}, author = {Huang, Neil K and B{\r u}zkov{\'a}, Petra and Matthan, Nirupa R and Djouss{\'e}, Luc and Hirsch, Calvin H and Kizer, Jorge R and Longstreth, W T and Mukamal, Kenneth J and Lichtenstein, Alice H} } @article {8787, title = {Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2021}, month = {2021 Jun 02}, abstract = {

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

RESULTS: The cohort comprised 5795 participants (age 73{\textpm}6, 42.2\% male, 14.3\% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69\% (probable/definite) to 4.67\% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88\% to 3.71\%. Of incident cases, about 85\% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95\% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95\% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95\% CI 0.23 to 0.81]).

CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319025}, author = {Owens, David S and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and Biggs, Mary L and Carlson, Selma D and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Kizer, Jorge R} } @article {8837, title = {Incidence, Determinants and Mortality of Heart Failure Associated With Medical-Surgical Procedures in Patients >= 65 Years of Age (from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {153}, year = {2021}, month = {2021 Aug 15}, pages = {71-78}, abstract = {

Heart failure (HF) and myocardial infarction are serious complications of major noncardiac surgery in older adults. Many factors can contribute to the development of HF during the postoperative period. The incidence of, and risk factors for, procedure-associated heart failure (PHF) occurring at the time of, or shortly after, medical procedures in a population-based sample >= 65 years of age have not been fully characterized, particularly in comparison with HF not proximate to medical procedures. This analysis comprises 5,121 men and women free of HF at baseline from the Cardiovascular Health Study who were followed up for 12.0 years (median). HF events were documented by self-report at semi-annual contacts and confirmed by a formal adjudication committee using a review of the participants{\textquoteright} medical records and standardized criteria for HF. Incident HF events were additionally adjudicated as either being related or unrelated to a medical procedure (PHF and non-PHF, respectively). We estimated cause-specific hazards ratios for the association of covariates with PHF and non-PHF. There were 1,728 incident HF events in the primary analysis: 168 (10\%) classified as PHF, 1,526 (88\%) as non-PHF, and 34 unclassified (2\%). For those 1,045 participants in whom LV ejection fraction was known at the time of the HF event, it was >=45\% in 89 of 118 participants (75\%) with PHF, compared to 517 of 927 participants (55\%) with non-PHF (p < 0.001). Increased age, male gender, diabetes, and angina at baseline were associated with both PHF and non-PHF (range of hazard ratios (HR): 1.04-2.05]. Being Black was inversely associated with PHF [HR: 0.46, 95\% confidence interval: 0.25-0.86]. Participants with increased age, without baseline angina, and with baseline LVEF<55\% were at a significantly lower risk for PHF compared to non-PHF. Among those with PHF, surgical procedures-including cardiac, orthopedic, gastrointestinal, vascular, and urologic-comprised 83.3\%, while percutaneous procedures comprised 8.9\% (including 6.5\% represented by cardiac catheterizations and pacemaker placements). Another group composed of a variety of procedures commonly requiring large fluid volume administration comprised 7.7\%. There was a lower all-cause 30-day mortality in the PHF versus the non-PHF group (2.2\% vs 5.7\%), with a nonsignificant odds ratio of 0.39 in a minimally adjusted model. When individuals with prior myocardial infarction (MI) were excluded in a sensitivity analysis, the proportion of incident HF with concurrent MI was greater~for PHF (32.9\%) than for non-PHF (19.8\%). In conclusion, PHF in older adults is a common entity with relatively low 30-day mortality. Baseline angina, lower age, and LVEF >= 55\% were associated with a higher risk of PHF compared to non-PHF. Being Black was associated with a lower risk of PHF and PHF as a proportion of HF was lower in Black than in non-Black participants. Compared to non-PHF, PHF more frequently presented with concurrent MI and with preserved LV ejection fraction.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2021.05.017}, author = {Shah, Monali and Rodriguez, Carlos J and Bartz, Traci M and Lyles, Mary F and Kizer, Jorge R and Aurigemma, Gerard P and Gardin, Julius M and Gottdiener, John S} } @article {8665, title = {Individual non-esterified fatty acids and incident atrial fibrillation late in life.}, journal = {Heart}, year = {2021}, month = {2021 Jan 22}, abstract = {

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.

METHODS: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.

RESULTS: The study sample included 1872 participants (age 77.7{\textpm}4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95\% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95\% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.

CONCLUSIONS: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2020-317929}, author = {Pellegrini, Cara N and B{\r u}zkov{\'a}, Petra and Lichtenstein, Alice H and Matthan, Nirupa R and Ix, Joachim H and Siscovick, David S and Heckbert, Susan R and Tracy, Russell P and Mukamal, Kenneth J and Djouss{\'e}, Luc and Kizer, Jorge R} } @article {8668, title = {Nonesterified Fatty Acids and Kidney Function Decline in Older Adults: Findings From the Cardiovascular Health Study.}, journal = {Am J Kidney Dis}, year = {2021}, month = {2021 Feb 03}, abstract = {

RATIONALE \& OBJECTIVE: Circulating non-esterified fatty acids (NEFAs) make up a small portion of circulating lipids but are a metabolically important energy source. Excessive circulating NEFAs may contribute to lipotoxicity in many tissues, including the kidneys. We investigated the relationship between total circulating NEFA concentration and kidney outcomes in older, community-dwelling adults.

STUDY DESIGN: Prospective cohort study.

SETTING \& PARTICIPANTS: 4,698 participants >=65 years of age in the Cardiovascular Health Study who underwent total fasting serum NEFA concentration measurements in 1992-1993.

EXPOSURE: Fasting serum NEFA concentration at one timepoint.

OUTCOMES: Three primary outcomes: estimated glomerular filtration rate (eGFR) decline of >30\%; the composite of eGFR decline >=30\% or kidney failure with replacement therapy (KFRT); and change in eGFR. These outcomes were assessed over 4- and 13-year periods.

ANALYTICAL APPROACH: Logistic regression for the dichotomous outcomes and mixed effects models for the continuous outcome, with sequential adjustment for baseline covariates. Inverse probability of attrition weighting was implemented to account for informative attrition during the follow-up periods.

RESULTS: Serum NEFA concentrations were not independently associated with kidney outcomes. In unadjusted and partially adjusted analyses, the highest quartile of serum NEFA concentration (compared to lowest) was associated with a higher risk of >=30\% eGFR decline at 4 years and faster rate of decline of eGFR. No associations were evident after adjustment for comorbidities, lipid levels, insulin sensitivity, medications, and vital signs: odds ratio 1.33 (95\%CI 0.83-2.13); estimated glomerular filtration rate change per year, Q4 vs Q1: -0.15 ml/min/1.73m/year (95\%CI -0.36 to 0.06).

LIMITATIONS: Single NEFA measurements, no measurements of post-glucose load NEFA concentrations or individual NEFA species, no measurement of baseline urine albumin.

CONCLUSIONS: A single fasting serum NEFA concentration was not independently associated with long-term adverse kidney outcomes in a cohort of older community-living adults.

}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2020.11.030}, author = {Walther, Carl P and Ix, Joachim H and Biggs, Mary L and Kizer, Jorge R and Navaneethan, Sankar D and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {8704, title = {Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.}, journal = {Cardiology}, year = {2021}, month = {2021 Feb 25}, pages = {1-8}, abstract = {

BACKGROUND: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

OBJECTIVE: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

METHODS: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

RESULTS: The mean age was 77.7 {\textpm} 4.4 years, and 38.8\% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95\% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

CONCLUSION: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.

}, issn = {1421-9751}, doi = {10.1159/000513917}, author = {Djouss{\'e}, Luc and Biggs, Mary L and Matthan, Nirupa R and Ix, Joachim H and Fitzpatrick, Annette L and King, Irena and Lemaitre, Rozenn N and McKnight, Barbara and Kizer, Jorge R and Lichtenstein, Alice H and Mukamal, Kenneth J and Siscovick, David S} } @article {8911, title = {Serum Non-Esterified Fatty Acids, Carotid Artery Intima-Media Thickness and Flow-Mediated Dilation in Older Adults: The Cardiovascular Health Study (CHS).}, journal = {Nutrients}, volume = {13}, year = {2021}, month = {2021 Aug 31}, abstract = {

Elevated common carotid artery intima-media thickness (carotid IMT) and diminished flow-mediated dilation (FMD) are early subclinical indicators of atherosclerosis. Serum total non-esterified fatty acid (NEFA) concentrations have been positively associated with subclinical atherosclerosis. The relations between individual NEFA, carotid IMT and FMD have as yet to be assessed. We investigated the associations between fasting serum individual NEFA, carotid IMT and FMD among Cardiovascular Health Study (CHS) participants with ( = 255 for carotid IMT, 301 for FMD) or without ( = 1314 for carotid IMT, 1462 for FMD) known atherosclerotic cardiovascular disease (ASCVD). Using archived samples (fasting) collected from 1996-1997 (baseline), 35 individual NEFAs were measured using gas chromatography. Carotid IMT and estimated plaque thickness (mean of maximum internal carotid IMT) were determined in 1998-1999. FMD was measured in 1997-1998. Linear regression adjusted by the Holm-Bonferroni method was used to assess relations between individual NEFA, carotid IMT and FMD. In multivariable adjusted linear regression models per SD increment, the non-esterified fatty acid conjugated linoleic acid (-18:2 CLA) was positively associated with carotid IMT [β (95\% CI): 44.8 (19.2, 70.4), = 0.025] among participants with, but not without, ASCVD [2.16 (-6.74, 11.5), = 1.000]. Non-esterified -palmitoleic acid (16:1n-7) was positively associated with FMD [19.7 (8.34, 31.0), = 0.024] among participants without, but not with ASCVD. No significant associations between NEFAs and estimated plaque thickness were observed. In older adults, serum non-esterified CLA and palmitoleic acid were positively associated with carotid IMT and FMD, respectively, suggesting potential modifiable biomarkers for arteriopathy.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Biomarkers, Brachial Artery, Carotid Artery, Common, Carotid Intima-Media Thickness, Dilatation, Fatty Acids, Monounsaturated, Fatty Acids, Nonesterified, Female, Humans, Linoleic Acid, Male, Regional Blood Flow, Risk Factors, Ultrasonography}, issn = {2072-6643}, doi = {10.3390/nu13093052}, author = {Huang, Neil K and B{\r u}zkov{\'a}, Petra and Matthan, Nirupa R and Djouss{\'e}, Luc and Kizer, Jorge R and Mukamal, Kenneth J and Polak, Joseph F and Lichtenstein, Alice H} } @article {8825, title = {Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, year = {2021}, month = {2021 Aug 07}, abstract = {

PURPOSE: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

METHODS: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

RESULTS: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6~mg/dl) was associated with greater grip strength (kg force) β~=~0.44 [0.16, 0.72]; p~=~0.002) and higher lean muscle mass (kg) (β~=~0.43 [0.08, 0.78]; p~=~0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95\% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p~=~0.65).

CONCLUSION: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.

}, issn = {1532-5415}, doi = {10.1111/jgs.17388}, author = {Barzilay, Joshua I and B{\r u}zkov{\'a}, Petra and Shlipak, Michael G and Lyles, Mary F and Bansal, Nisha and Garimella, Pranav S and Ix, Joachim H and Kizer, Jorge R and Strotmeyer, Elsa S and Djouss{\'e}, Luc and Biggs, Mary L and Siscovick, David and Mukamal, Kenneth J} } @article {9154, title = {The association of aortic valve sclerosis, aortic annulus increased reflectivity, and mitral annular calcification with subsequent aortic stenosis in older individuals. Findings from the Cardiovascular Health Study.}, journal = {J Am Soc Echocardiogr}, year = {2022}, month = {2022 Sep 09}, abstract = {

BACKGROUND: While aortic valve sclerosis (AVS) is well-described as preceding aortic stenosis (AS), the association of AS with antecedent mitral aortic annular calcification and aortic annulus increased reflectivity (MAC and AAIR, respectively) has not been characterized. In a population-based prospective study, we evaluated whether MAC, AAIR, and AVS are associated with the risk of incident AS.

METHODS: Among participants of the Cardiovascular Health Study (CHS) free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three were evaluated in 3041 participants. Cox proportional hazards regression was used to assess the association between the presence of calcification and the incidence of moderate/severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS.

RESULTS: Over a median follow-up of 11.5 years (IQR 6.7 to 17.0), 110 cases of incident moderate/severe AS were ascertained. Strong positive associations with incident moderate/severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (HR=2.90, 95\% CI=[1.95, 4.32], p<0.0005), AVS (HR=2.20, 95\% CI=[1.44, 3.37], p<0.0005), MAC (HR=1.67, 95\% CI=[1.14, 2.45], p=0.008), and the combination of MAC, AAIR, and AVS (HR=2.50, 95\% CI=[1.65, 3.78], p<0.0005). In a secondary analysis, the risk of AS increased with the number of sites at which calcification was present.

CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of MAC, AAIR, and AVS with incident moderate/severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS, and potential inclusion in the routine assessment by transthoracic echocardiography.

}, issn = {1097-6795}, doi = {10.1016/j.echo.2022.08.013}, author = {Barasch, Eddy and Gottdiener, John S and Tressel, William and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and DeFilippi, Christopher and Biggs, Mary L and Psaty, Bruce M and Kizer, Jorge R and Owens, David} } @article {9175, title = {Association of immune cell subsets with incident heart failure in two population-based cohorts.}, journal = {ESC Heart Fail}, year = {2022}, month = {2022 Sep 12}, abstract = {

AIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].

METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0~{\textpm}~10.4~years with 51\% women, and in the CHS cohort, it was 79.6~{\textpm}~4.4~years with 62\% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95\% CI 0.83-0.99), P~=~0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95\% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.

CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

}, issn = {2055-5822}, doi = {10.1002/ehf2.14140}, author = {Sinha, Arjun and Sitlani, Colleen M and Doyle, Margaret F and Fohner, Alison E and B{\r u}zkov{\'a}, Petra and Floyd, James S and Huber, Sally A and Olson, Nels C and Njoroge, Joyce N and Kizer, Jorge R and Delaney, Joseph A and Shah, Sanjiv S and Tracy, Russell P and Psaty, Bruce and Feinstein, Matthew} } @article {9155, title = {The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {45}, year = {2022}, month = {2022 10 01}, pages = {2376-2382}, abstract = {

OBJECTIVE: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes.

RESEARCH DESIGN AND METHODS: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change.

RESULTS: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change.

CONCLUSIONS: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action.

}, keywords = {Aged, Autonomic Nervous System, Blood Glucose, Diabetes Mellitus, Glucose, Heart Rate, Humans, Hypotension, Orthostatic, Insulin Resistance}, issn = {1935-5548}, doi = {10.2337/dc22-0553}, author = {Barzilay, Joshua I and Tressel, William and Biggs, Mary L and Stein, Phyllis K and Kizer, Jorge R and Shitole, Sanyog G and Bene-Alhasan, Yakubu and Mukamal, Kenneth J} } @article {9153, title = {The Associations of Individual and Subclasses of Non-Esterified Fatty Acids with Disability, and Mobility Limitation in Older Adults: the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2022}, month = {2022 Sep 26}, abstract = {

BACKGROUND: We sought to determine the associations between individual non-esterified fatty acids (NEFAs) and disability and mobility limitation.

METHODS: We studied 1734 participants in the Cardiovascular Health Study (CHS), an ongoing population-based cohort study of community-living older American adults. We measured 35 individual NEFA species in fasting serum samples obtained at the 1996-1997 clinic visit. Using yearly assessments of activities of daily living and self-reported mobility, we identified participants with incident disability or mobility limitation during 15 years of follow-up. Cox proportional hazards regression models were used to determine the associations between per-SD increment in the individual NEFAs and incident disability and mobility limitations with adjustment for potential confounding factors.

RESULTS: Higher concentrations of total and a broad range of individual NEFA species were associated with risk of disability and mobility limitation [disability: HR per SD of total NEFA (SD=174.70) =1.11, 95\%CI=1.04-1.18, p=0.001; mobility limitation: HR per SD of total NEFA=1.09, 95\%CI=1.02-1.16, p=0.01). Among individual saturated NEFAs (SFAs), myristic (14:0) and palmitic (16:0) acids were significantly associated with higher risk of both disability and mobility limitations, but longer-chain FAs were not. Most individual monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFAs), and trans FAs were positively significantly associated with higher risks of both disability and mobility limitation. In contrast, most n-3 PUFA species were not associated with disability or mobility limitation.

CONCLUSIONS: Higher risks of disability and mobility limitation were observed for pro-inflammatory intermediate-chain SFAs, MUFAs, n-6 PUFAs, and trans FAs. Our findings indicated no significant association for anti-inflammatory n-3 PUFAs.

}, issn = {1758-535X}, doi = {10.1093/gerona/glac206}, author = {Ahiawodzi, Peter and B{\r u}zkov{\'a}, Petra and Lichtenstein, Alice H and Matthan, Nirupa R and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Arnold, Alice and Newman, Anne B and Siscovick, David and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {9043, title = {Body Composition and Incident Heart Failure in Older Adults: Results From 2 Prospective Cohorts.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 01 04}, pages = {e023707}, abstract = {

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

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

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

}, keywords = {Aged, Androgens, Cardiovascular Diseases, Dihydrotestosterone, Estradiol, Heart Failure, Humans, Male, Sex Hormone-Binding Globulin, Testosterone}, issn = {2047-9980}, doi = {10.1161/JAHA.122.026953}, author = {Njoroge, Joyce N and Tressel, William and Biggs, Mary L and Matsumoto, Alvin M and Smith, Nicholas L and Rosenberg, Emily and Hirsch, Calvin H and Gottdiener, John S and Mukamal, Kenneth J and Kizer, Jorge R} } @article {9259, title = {Dysregulated carbohydrate and lipid metabolism and risk of atrial fibrillation in advanced old age.}, journal = {Heart}, year = {2022}, month = {2022 Dec 22}, abstract = {

OBJECTIVE: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Fasting and postload levels of glucose and non-esterified fatty acids (NEFAs) reflect different facets of metabolic regulation. We sought to study their respective contributions to AF risk concurrently.

METHODS: We assessed levels of fasting and postload glucose and NEFA in the Cardiovascular Health Study to identify associations with AF incidence and, secondarily, with ECG parameters of AF risk available at baseline. Linear and Cox regressions were performed.

RESULTS: The study included 1876 participants (age 77.7{\textpm}4.4). During the median follow-up of 11.4 years, 717 cases of incident AF occurred. After adjustment for potential confounders, postload glucose showed an association with incident AF (HR per SD increment of postload glucose=1.11, 95\% CI 1.02 to 1.21, p=0.017). Both glucose measures, but not NEFA, were positively associated with higher P wave terminal force in V1 (PTFV1); the association remained significant only for postload glucose when the two measures were entered together (β per SD increment=138 μV{\textperiodcentered}ms, 95\% CI 15 to 260, p=0.028). Exploratory analyses showed significant interaction by sex for fasting NEFA (p=0.044) and postload glucose (p=0.015) relative to AF, with relationships stronger in women. For postload glucose, the association with incident AF was observed among women but not among men.

CONCLUSIONS: Among older adults, postload glucose was positively associated with incident AF, with consistent findings for PTFV1. In exploratory analyses, the relationship with AF appeared specific to women. These findings require further study but suggest that interventions to address postprandial dysglycaemia late in life might reduce AF.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2022-321633}, author = {Pellegrini, Cara N and B{\r u}zkov{\'a}, Petra and Oesterle, Adam and Heckbert, Susan R and Tracy, Russell P and Siscovick, David S and Mukamal, Kenneth J and Djouss{\'e}, Luc and Kizer, Jorge R} } @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 {9295, title = {Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults.}, journal = {Am J Epidemiol}, volume = {191}, year = {2022}, month = {2022 Jun 27}, pages = {1235-1247}, abstract = {

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio~= 1.18, 95\% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio~= 1.12, 95\% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

}, keywords = {Aged, Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Fatty Acids, Nonesterified, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Prospective Studies}, issn = {1476-6256}, doi = {10.1093/aje/kwac044}, author = {Shitole, Sanyog G and Biggs, Mary L and Ix, Joachim H and Fretts, Amanda M and Tracy, Russell P and Siscovick, David S and Djouss{\'e}, Luc and Mukamal, Kenneth J and Kizer, Jorge R} } @article {9092, title = {Glucose dysregulation and subclinical cardiac dysfunction in older adults: The Cardiovascular Health Study.}, journal = {Cardiovasc Diabetol}, volume = {21}, year = {2022}, month = {2022 Jun 20}, pages = {112}, abstract = {

OBJECTIVE: We evaluated whether measures of glucose dysregulation are associated with subclinical cardiac dysfunction, as assessed by speckle-tracking echocardiography, in an older population.

METHODS: Participants were men and women in the Cardiovascular Health Study, age 65+ years and without coronary heart disease, atrial fibrillation, or heart failure at baseline. We evaluated fasting insulin resistance (IR) with the homeostatic model of insulin resistance (HOMA-IR) and estimated the Matsuda insulin sensitivity index (ISI) and insulin secretion with an oral glucose tolerance test. Systolic and diastolic cardiac mechanics were measured with speckle-tracking analysis of echocardiograms. Multi-variable adjusted linear regression models were used to investigate associations of insulin measures and cardiac mechanics.

RESULTS: Mean age for the 2433 included participants was 72.0~years, 33.6\% were male, and 3.7\% were black. After adjustment for age, sex, race, site, speckle-tracking analyst, echo image and quality score, higher HOMA-IR, lower Matsuda ISI, and higher insulin secretion were each associated with worse left ventricular (LV) longitudinal strain and LV early diastolic strain rate (p-value < 0.005); however, associations were significantly attenuated after adjustment for waist circumference, with the exception of Matsuda ISI and LV longitudinal strain (increase in strain per standard deviation increment in Matsuda ISI = 0.18; 95\% confidence interval = 0.03-0.33).

CONCLUSION: In this cross-sectional study of older adults, associations of glucose dysregulation with subclinical cardiac dysfunction were largely attenuated after adjusting for central adiposity.

}, keywords = {Aged, Cross-Sectional Studies, Female, Glucose, Humans, Insulin Resistance, Male, Ventricular Dysfunction, Left, Ventricular Function, Left}, issn = {1475-2840}, doi = {10.1186/s12933-022-01547-z}, author = {Garg, Parveen K and Biggs, Mary L and Kizer, Jorge R and Shah, Sanjiv J and Psaty, Bruce and Carnethon, Mercedes and Gottdiener, John S and Siscovick, David and Mukamal, Kenneth J} } @article {9025, title = {Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults.}, journal = {JAMA Netw Open}, volume = {5}, year = {2022}, month = {2022 Mar 01}, pages = {e225012}, abstract = {

Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.

Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).

Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.

Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).

Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.

Results: Of 4125 individuals, 0.1\% (n = 3) were Asian or Pacific Islander, 4.4\% (n = 183) were Black, 0.3\% (n = 12) were Native American, 95.0\% (n = 3918) were White, and 0.2\% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60\%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4\%]; and 3942 individuals of other races and ethnicitites [95.6\%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95\% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95\% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95\% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95\% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5\% for interleukin 18 to 14.2\% for C-reactive protein, and 16.1\% for their primary principal component.

Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.

}, keywords = {Adult, Aged, Cardiovascular Diseases, Cohort Studies, Dietary Fiber, Female, Humans, Inflammation, Middle Aged, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2022.5012}, author = {Shivakoti, Rupak and Biggs, Mary L and Djouss{\'e}, Luc and Durda, Peter Jon and Kizer, Jorge R and Psaty, Bruce and Reiner, Alex P and Tracy, Russell P and Siscovick, David and Mukamal, Kenneth J} } @article {9170, title = {Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts.}, journal = {J Am Heart Assoc}, volume = {11}, year = {2022}, month = {2022 08 02}, pages = {e024012}, abstract = {

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

}, keywords = {Atherosclerosis, Cardiovascular Diseases, Cohort Studies, Glycation End Products, Advanced, Humans, Middle Aged, Risk Factors}, issn = {2047-9980}, doi = {10.1161/JAHA.121.024012}, author = {Lamprea-Montealegre, Julio A and Arnold, Alice M and McClelland, Robyn L and Mukamal, Kenneth J and Djouss{\'e}, Luc and Biggs, Mary L and Siscovick, David S and Tracy, Russell P and Beisswenger, Paul J and Psaty, Bruce M and Ix, Joachim H and Kizer, Jorge R} } @article {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 {8974, title = {Relation of Cigarette Smoking and Heart Failure in Adults >=65~Years of Age (From the Cardiovascular Health Study).}, journal = {Am J Cardiol}, year = {2022}, month = {2022 Jan 16}, abstract = {

Cigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95\% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95\% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2021.12.021}, author = {Gottdiener, John S and B{\r u}zkov{\'a}, Petra and Kahn, Peter A and DeFilippi, Christopher and Shah, Sanjiv and Barasch, Eddy and Kizer, Jorge R and Psaty, Bruce and Gardin, Julius M} } @article {9248, title = {Sex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.}, journal = {J Am Geriatr Soc}, year = {2022}, month = {2022 Nov 05}, abstract = {

BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.

METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n~=~2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n~=~1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.

RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR~=~1.41 per 0.1-g/cm decrement [95\% CI~=~1.23-1.62]), and showed the same to be true for White men (HR~=~1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men.

CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

}, issn = {1532-5415}, doi = {10.1111/jgs.18121}, author = {Gao, Hans and Patel, Sheena and Fohtung, Raymond B and Cawthon, Peggy M and Newman, Anne B and Cauley, Jane A and Carbone, Laura and Chaves, Paulo H M and Stein, Phyllis K and Civitelli, Roberto and Kizer, Jorge R} } @article {9320, title = {Cardiac Mechanics and Kidney Function Decline in the Cardiovascular Health Study.}, journal = {Kidney360}, year = {2023}, month = {2023 Mar 08}, abstract = {

BACKGROUND: Clinical heart failure frequently coexists with chronic kidney disease (CKD) and may precipitate kidney function decline. However, whether earlier-stage myocardial dysfunction assessable by speckle tracking echocardiography is a contributor to kidney function decline remains unknown.

METHODS: We studied 2135 Cardiovascular Health Study (CHS) participants who were free of clinical heart failure and had Year 2-baseline 2D speckle tracking echocardiography and two measurements of estimated glomerular filtration rate (eGFR) (Year 2 and Year 9). "Archival" speckle tracking of digitized echocardiogram videotapes was utilized to measure left ventricular longitudinal strain (LVLS), LV early diastolic strain rate (EDSR), left atrial reservoir strain (LARS), right ventricular free wall strain (RVFWS), and mitral annular velocity (e{\textquoteright}). Multivariable Poisson regression models that adjusted for demographics and cardiovascular risk factors were used to investigate the independent associations of cardiac mechanics indices and decline in kidney function defined as a 30\% decline in eGFR over 7 years.

RESULTS: In risk factor (RF) models LVLS, EDSR, RVFWS, and e{\textquoteright} were all significantly associated with the prevalence of kidney disease. After multivariable adjustment, left atrial dysfunction (RR 1.18 [95\% CI 1.01, 1.38] per SD lower LARS] and left ventricular diastolic dysfunction (RR 1.21 [95\% CI 1.04, 1.41] per SD lower EDSR) were each significantly associated with 30\% decline in eGFR.

CONCLUSIONS: Subclinical myocardial dysfunction suggesting abnormal diastolic function detected by 2D speckle-tracking echocardiography was independently associated with decline in kidney function over time. Further studies are needed to understand the mechanisms of these associations and to test whether interventions that may improve subclinical myocardial dysfunction can prevent decline of kidney function.

}, issn = {2641-7650}, doi = {10.34067/KID.0000000000000100}, author = {Mehta, Rupal and B{\r u}zkov{\'a}, Petra and Patel, Harnish and Cheng, Jeanette and Kizer, Jorge R and Gottdiener, John S and Psaty, Bruce and Khan, Sadiya S and Ix, Joachim H and Isakova, Tamara and Shlipak, Michael G and Bansal, Nisha and Shah, Sanjiv J} } @article {9481, title = {Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2023}, month = {2023 Aug 25}, abstract = {

BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8.

METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults.

RESULTS: In 2,599 participants (age 75.2{\textpm}4.3) followed for 10.8{\textpm}5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks and lower kidney function.

CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-βsuperfamily pathways as potential therapeutic targets.

}, issn = {1758-535X}, doi = {10.1093/gerona/glad206}, author = {Kizer, Jorge R and Patel, Sheena and Ganz, Peter and Newman, Anne B and Bhasin, Shalender and Lee, Se-Jin and Cawthon, Peggy M and LeBrasseur, Nathan and Shah, Sanjiv J and Psaty, Bruce M and Tracy, Russell P and Cummings, Steven R} } @article {9582, title = {The determinants of fasting and post-load non-esterified fatty acids in older adults: The cardiovascular health study.}, journal = {Metabol Open}, volume = {20}, year = {2023}, month = {2023 Dec}, pages = {100261}, abstract = {

AIM: Non-esterified fatty acids (NEFA) are potential targets for prevention of key cardiometabolic diseases of aging, but their population-level correlates remain uncertain. We sought to identify modifiable factors associated with fasting and post-load NEFA levels in older adults.

METHODS: We used linear regression to determine the cross-sectional associations of demographic, anthropometric, and lifestyle characteristics and medication use with serum fasting and post-load NEFA concentrations amongst community-dwelling older adults enrolled in the Cardiovascular Health Study (n~=~1924).

RESULTS: Fasting NEFA levels generally demonstrated a broader set of determinants, while post-load NEFA were more consistently associated with metabolic factors. Waist circumference and weight were associated with higher fasting and post-load NEFA. Cigarette smoking and caffeine intake were associated with lower levels of both species, and moderate alcohol intake was associated with higher fasting levels whereas greater consumption was associated with lower post-load levels. Unique factors associated with higher fasting NEFA included female sex, higher age, loop and thiazide diuretic use and calcium intake, while factors associated with lower fasting levels included higher educational attainment, beta-blocker use, and protein intake. Hours spent sleeping during the daytime were associated with higher post-load NEFA, while DASH score was associated with lower levels.

CONCLUSION: Fasting and post-load NEFA have both common and unique modifiable risk factors, including sociodemographics, anthropometric, medications, and diet. Post-load NEFA were particularly sensitive to metabolic factors, while a broader range of determinants were associated with fasting levels. These factors warrant study as targets for lowering levels of NEFA in older adults.

}, issn = {2589-9368}, doi = {10.1016/j.metop.2023.100261}, author = {Bene-Alhasan, Yakubu and Siscovick, David S and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @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 {9237, title = {Inflammation and Incident Conduction Disease.}, journal = {J Am Heart Assoc}, volume = {12}, year = {2023}, month = {2023 Jan 03}, pages = {e027247}, keywords = {Cardiac Conduction System Disease, Electrocardiography, Heart Block, Humans, Inflammation}, issn = {2047-9980}, doi = {10.1161/JAHA.122.027247}, author = {Frimodt-M{\o}ller, Emilie K and Gottdiener, John S and Soliman, Elsayed Z and Kizer, Jorge R and Vittinghoff, Eric and Psaty, Bruce M and Biering-S{\o}rensen, Tor and Marcus, Gregory M} } @article {9288, title = {Lifestyle habits associated with cardiac conduction disease.}, journal = {Eur Heart J}, year = {2023}, month = {2023 Jan 20}, abstract = {

AIMS: Cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. Research to identify modifiable risk factors has been scant.

METHODS AND RESULTS: Data from the Cardiovascular Health Study, a population-based cohort study of adults >= 65 years with annual 12-lead electrocardiograms obtained over 10 years, were utilized to examine relationships between baseline characteristics, including lifestyle habits, and conduction disease. Of 5050 participants (mean age 73 {\textpm} 6 years; 52\% women), prevalent conduction disease included 257 with first-degree atrioventricular block, 99 with left anterior fascicular block, 9 with left posterior fascicular block, 193 with right bundle branch block (BBB), 76 with left BBB, and 102 with intraventricular block at baseline. After multivariable adjustment, older age, male sex, a larger body mass index, hypertension, and coronary heart disease were associated with a higher prevalence of conduction disease, whereas White race and more physical activity were associated with a lower prevalence. Over a median follow-up on 7 (interquartile range 1-9) years, 1036 developed incident conduction disease. Older age, male sex, a larger BMI, and diabetes were each associated with incident conduction disease. Of lifestyle habits, more physical activity (hazard ratio 0.91, 95\% confidence interval 0.84-0.98, P = 0.017) was associated with a reduced risk, while smoking and alcohol did not exhibit a significant association.

CONCLUSION: While some difficult to control comorbidities were associated with conduction disease as expected, a readily modifiable lifestyle factor, physical activity, was associated with a lower risk.

}, issn = {1522-9645}, doi = {10.1093/eurheartj/ehac799}, author = {Frimodt-M{\o}ller, Emilie K and Soliman, Elsayed Z and Kizer, Jorge R and Vittinghoff, Eric and Psaty, Bruce M and Biering-S{\o}rensen, Tor and Gottdiener, John S and Marcus, Gregory M} } @article {9284, title = {Non-esterified fatty acids and risk of peripheral artery disease in older adults: The cardiovascular health study.}, journal = {Atherosclerosis}, year = {2023}, month = {2023 Jan 29}, abstract = {

BACKGROUND AND AIMS: Non-esterified fatty acids have been implicated in the pathogenesis of diabetes and cardiovascular disease. No longitudinal study has assessed their effects on peripheral artery disease (PAD). We determined the relationships between NEFAs and incident clinical PAD and abnormal ankle-brachial index (ABI) in a population-based cohort of older persons.

METHODS: We evaluated 4575 community living participants aged >65 years who underwent measurement of circulating NEFAs in fasting specimens and ABI in 1992-1993. Participants were assessed annually for clinical PAD until 2015 and underwent repeat ABI in 1998-1999. We used Cox proportional hazards regression to model the associations between NEFAs and risk of clinical PAD and logistic regression to model the associations of NEFAs with incident abnormal ABI.

RESULTS: Mean age was 74.8 years, 59\% were female, and 17\% were Black. NEFAs were associated with higher risk of clinical PAD in unadjusted and adjusted models. The adjusted hazard ratios for incident clinical PAD were 1.51 (95\%CI~=~1.06-2.13, p~=~0.02) across extreme tertiles, and 1.14 (95\%CI~=~0.99-1.31, p~=~0.08) per standard deviation higher NEFA. The corresponding odds ratios for abnormal ABI were 0.95 (95\%CI~=~0.69-1.32, p~=~0.76) across extreme tertiles, and 1.03 (95\%CI~=~0.89-1.20, p~=~0.68) per standard deviation higher NEFA. Relationships appeared similar irrespective of sex, race, or pre-existing cardiovascular disease, but were stronger later than earlier in follow-up.

CONCLUSIONS: Higher serum levels of NEFAs are significantly associated with increased likelihood of clinical PAD over long-term follow-up but not with 6-year decline in ABI. NEFAs may offer a potential target for intervention against clinical PAD.

}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2023.01.020}, author = {Ahiawodzi, Peter and Solaru, Khendi White and Chaves, Paulo H M and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Newman, Anne and Siscovick, David and Djouss{\'e}, Luc and Mukamal, Kenneth J} } @article {9536, title = {Proteomic prediction of incident heart failure and its main subtypes.}, journal = {Eur J Heart Fail}, year = {2023}, month = {2023 Nov 08}, abstract = {

AIM: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables.

METHODS AND RESULTS: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with nonparametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on NT-proBNP and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study (CHS).

CONCLUSION: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to eight years, with predictor performance significantly improving for events occurring less than one year ahead, a finding replicated in an external cohort study. This article is protected by copyright. All rights reserved.

}, issn = {1879-0844}, doi = {10.1002/ejhf.3086}, author = {Emilsson, Valur and Jonsson, Brynjolfur G and Austin, Thomas R and Gudmundsdottir, Valborg and Axelsson, Gisli T and Frick, Elisabet A and Jonmundsson, Thorarinn and Steindorsdottir, Anna E and Loureiro, Joseph and Brody, Jennifer A and Aspelund, Thor and Launer, Lenore J and Thorgeirsson, Gudmundur and Kortekaas, Kirsten A and Lindeman, Jan H and Orth, Anthony P and Lamb, John R and Psaty, Bruce M and Kizer, Jorge R and Jennings, Lori L and Gudnason, Vilmundur} } @article {9416, title = {Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2023}, month = {2023 Jul 18}, abstract = {

OBJECTIVES: Calcific aortic stenosis (AS) is the most common valvular disease in older adults, yet its risk factors remain insufficiently studied in this population. Such studies are necessary to enhance understanding of mechanisms, disease management and therapeutics.

METHODS: The Cardiovascular Health Study is a population-based investigation of older adults that completed adjudication of incident AS over long-term follow-up. We evaluated traditional cardiovascular risk factors or disease, as well as novel risk factors from lipid, inflammatory and mineral metabolism pathways, in relation to incident moderate or severe AS (including AS procedures) and clinically significant AS (severe AS, including procedures).

RESULTS: Of 5390 participants (age 72.9{\textpm}5.6 years, 57.6\% female, 12.5\% black), 287 developed moderate or severe AS, and 175 clinically significant AS, during median follow-up of 13.1 years. After full adjustment, age (HR=1.66 per SD (95\% CI=1.45, 1.91)), male sex (HR=1.41 (1.06, 1.87)), diabetes (HR=1.53 (1.10, 2.13)), coronary heart disease (CHD, HR=1.36 (1.01, 1.84)), lipoprotein-associated phospholipase-A (LpPLA) activity (HR=1.21 per SD (1.07, 1.37)) and sCD14 (HR=1.16 per SD (1.01, 1.34)) were associated with incident moderate/severe AS, while black race demonstrated an inverse association (HR=0.40 (0.24, 0.65)), and creatinine-based estimated glomerular filtration rate (eGFR) showed a U-shaped relationship. Findings were similar for clinically significant AS, although CHD and sCD14 fell short of significance, but interleukin-(IL) 6 showed a positive association.

CONCLUSION: This comprehensive evaluation of risk factors for long-term incidence of AS identified associations for diabetes and prevalent CHD, LpPLA activity, sCD14 and IL-6, and eGFR. These factors may hold clues to biology, preventive efforts and potential therapeutics for those at highest risk.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2023-322709}, author = {Massera, Daniele and Bartz, Traci M and Biggs, Mary L and Sotoodehnia, Nona and Reiner, Alexander P and Semba, Richard D and Gottdiener, John S and Psaty, Bruce M and Owens, David S and Kizer, Jorge R} } @article {9574, title = {Association of thyroid dysfunction in individuals >= 65 years of age with subclinical cardiac abnormalities.}, journal = {J Clin Endocrinol Metab}, year = {2024}, month = {2024 Jan 06}, abstract = {

CONTEXT: The relationship between thyroid dysfunction and measures of myocardial disease in older individuals remains to be defined.

OBJECTIVE: To evaluate the impact of thyroid dysfunction on structure and function of the left-heart chambers and blood markers of cardiac disease.

DESIGN: Cross-sectional analysis.

SETTING: The Cardiovascular Health Study, a community-based cohort of older individuals recruited from four urban areas in the United States.

PATIENTS: Of 3163 participants studied, 2477 were euthyroid, 465 had subclinical hypothyroidism (SCH), 47 overt hypothyroidism (OH), 45 endogenous (endo) subclinical hyperthyroidism (endo-SCT), and 129 had exogenous (exo) SCT due to thyroid hormone supplementation.

INTERVENTIONS: Clinical evaluation, blood sampling and biomarker measurement, 2-dimensional and speckle-tracking echocardiography.

MAIN OUTCOME MEASURE(S): Left heart myocardial deformation, circulating biomarkers of diastolic overload (NT-proBNP), fibrosis (sST2, gal-3), and cardiomyocyte injury (hs-cTnT).

RESULTS: SCH was associated with higher NT-proBNP (beta = 0.17, p = 0.004), whereas OH was associated with higher hs-cTnT (beta = 0.29, p = 0.005). There were also suggestive associations of SCH with higher sST2, as well as endo-SCT with higher gal-3 and lower (worse) left atrial reservoir strain. Left ventricular longitudinal strain and end-diastolic strain rate did not differ significantly from euthyroid participants in SCH, OH, or exo-SCT.

CONCLUSIONS: In this free-living elderly cohort, subclinical and overt hypothyroidism were associated with abnormalities of blood biomarkers consistent with diastolic overload and myocardial necrosis respectively, whereas subclinical hyperthyroidism tended to be associated with myocardial fibrosis and decreased left atrial strain. Our findings could represent stage B heart failure and illuminate distinct aspects of the pathobiology of heart disease related to thyroid gland dysfunction with potential clinical implications.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgae001}, author = {Barasch, Eddy and Gottdiener, John and B{\r u}zkov{\'a}, Petra and Cappola, Anne and Shah, Sanjiv and DeFilippi, Christopher and Gardin, Julius and Kizer, Jorge R} } @article {9615, title = {Iron Deficiency and Incident Heart Failure in Older Community-Dwelling Individuals.}, journal = {ESC Heart Fail}, year = {2024}, month = {2024 Feb 26}, abstract = {

AIMS: Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community-dwelling older adults irrespective of their kidney function.

METHODS: In this case-cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub-cohort [including 193 HF cases] and 221 additional HF cases [N~=~414 total HF cases]) aged >= 65~years without HF (41\% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as "iron replete" (27.3\%), "functional iron deficiency" (7.7\%), "iron deficiency" (11.8\%), "mixed iron deficiency" (5.6\%), "high iron" (9.3\%) and "non-classified" (38.1\%), consistent with prior studies.

RESULTS: Compared to older persons who were iron replete, those with iron deficiency were at higher risk of incident HF (HR 1.47; 1.02-2.11) in models adjusting for demographics, HF risk factors, and estimated glomerular filtration rate. Other iron categories did not associate with incident HF. The relationship of iron deficiency with incident HF did not differ by CKD status (interaction P value 0.2).

CONCLUSIONS: Among community-dwelling elders, iron deficiency is independently associated with incident HF, an association that was similar irrespective of CKD status. Our findings support conduct of clinical trials of iron replacement for prevention of HF in older adults with iron deficiency.

}, issn = {2055-5822}, doi = {10.1002/ehf2.14724}, author = {Sharma, Shilpa and Katz, Ronit and Chaves, Paulo H M and Hoofnagle, Andrew N and Kizer, Jorge R and Bansal, Nisha and Ganz, Tomas and Ix, Joachim H} } @article {9635, title = {Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.}, journal = {J Bone Miner Res}, year = {2024}, month = {2024 Jan 04}, abstract = {

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Tr{\o}ndelag Health Study) with circulating proteomics data (aptamer-based 5~K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 {\texttimes} 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

}, issn = {1523-4681}, doi = {10.1093/jbmr/zjad011}, author = {Austin, Thomas R and Fink, Howard A and Jalal, Diana I and T{\"o}rnqvist, Anna E and B{\r u}zkov{\'a}, Petra and Barzilay, Joshua I and Lu, Tianyuan and Carbone, Laura and Gabrielsen, Maiken E and Grahnemo, Louise and Hveem, Kristian and Jonasson, Christian and Kizer, Jorge R and Langhammer, Arnulf and Mukamal, Kenneth J and Gerszten, Robert E and Nethander, Maria and Psaty, Bruce M and Robbins, John A and Sun, Yan V and Skogholt, Anne Heidi and {\r A}svold, Bj{\o}rn Olav and Valderr{\'a}bano, Rodrigo J and Zheng, Jie and Richards, J Brent and Coward, Eivind and Ohlsson, Claes} }