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Midlife vascular disease increases risk for dementia and effects of vascular dysfunction on brain health differ between men and women. Elevated pulse pressure, a surrogate for arterial stiffness, contributes to cerebrovascular pathology and white matter damage that may advance cognitive aging; however, it remains unclear how associations between pulse pressure and neural integrity differ by sex and age. This study used restriction spectrum imaging to examine associations between pulse pressure and brain microstructure in community-dwelling women (N=88) and men (N=55), aged 56 to 97 (mean, 76.3) years. Restricted isotropic (presumed intracellular), hindered isotropic (presumed extracellular), neurite density, and free water diffusion were computed in white matter tracts and subcortical regions. After adjustment for age and sex, higher pulse pressure correlated with lower restricted isotropic diffusion in global white matter, with more pronounced associations in parahippocampal cingulum, as well as in thalamus and hippocampus. Subgroup analyses demonstrated stronger correlations between pulse pressure and restricted isotropic diffusion in association fibers for participants ≤75 years than for older participants, with stronger effects for women than men of this age group. Microstructure in parahippocampal cingulum and thalamus differed by pulse pressure level regardless of antihypertensive treatment. Increased pulse pressure may lead to widespread injury to white matter and subcortical structures, with greatest vulnerability for women in late middle to early older age. Restriction spectrum imaging could be useful for monitoring microstructural changes indicative of neuronal loss or shrinkage, demyelination, or inflammation that accompany age-related cerebrovascular dysfunction.

Context: Observational studies show discordant links between endogenous testosterone levels and cardiovascular diseases (CVD).Objective: We assessed whether sex hormones and sex hormone-binding globulin (SHBG) are associated with CVD in community-dwelling elderly men.Design setting and participants: Prospective study of incident CVD among 552 men ≥ 65 years in the MrOS Sleep Study without prevalent CVD and no testosterone therapy at baseline.Outcomes: Fasting serum levels of total testosterone and estradiol were measured using liquid chromatography-mass spectrometry, and SHBG by chemiluminescent substrate. The association of sex hormones and SHBG with incident coronary heart disease (CHD), cerebrovascular (stroke and transient ischemic attack) and peripheral arterial disease (PAD) events were assessed by quartile and per SD increase in proportional hazards models.Results: After 7.4 years, 137 men (24.8%) had at least 1 CVD event: 90 CHD, 45 cerebrovascular and 26 PAD. The risk of incident CVD events was not associated with quartiles of baseline sex hormones or SHBG (all P ≥ 0.16). For +1 SD in total testosterone, the multivariate-adjusted hazard ratio was 1.04 (95% CI, 0.80-1.34) for CHD, 0.86 (0.60-1.25) for cerebrovascular, and 0.81 (0.52-1.26) for PAD events. When analyzed as continuous variables or comparing highest to low quartile, levels of bioavailable testosterone, total estradiol, testosterone/estradiol ratio and SHBG were not associated with CVD events.Conclusions: In community-dwelling elderly men, endogenous levels of testosterone, estradiol, and SHBG were not associated with increased risk of CHD, cerebrovascular, or PAD events. These results are limited by the small number of events and should be explored in future studies.

Publisher's version (útgefin grein), Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need., The work of the co-ordinating centre was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/ 002), British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). The Emerging Risk Factor Collaboration’s website https://www.phpc.cam.ac.uk/ceu/erfc/list-of-studies/ has compiled a list provided by investigators of some of the funders of the component studies in this analysis. I.W. was supported by the Medical Research Council Unit Programme MC_UU_12023/21. M.K. is supported by the Netherlands Organization for Scientific Research (NWO) Veni grant (Veni, 91616079). J.P. is supported by Erasmus Mundus Western Balkans (ERAWEB), a project funded by the European Commission.

Key Points Question To what extent are established cardiovascular risk factors associated with risk of venous thromboembolism (VTE)? Findings In this analysis of individual participant data from the Emerging Risk Factors Collaboration and the UK Biobank including 1.1 million participants, among a panel of several established cardiovascular risk factors, older age, smoking, and greater adiposity were consistently associated with higher VTE risk. Meaning There is overlap in at least some of the major population determinants of important venous and arterial thrombotic diseases., This analysis of data from the Emerging Risk Factors Collaboration and the UK Biobank estimates the associations of major cardiovascular risk factors with venous thromboembolism., Importance It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. Design, Setting, and Participants This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. Exposures A panel of several established cardiovascular risk factors. Main Outcomes and Measures Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). Results Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. Conclusions and Relevance Older age, smoking, and adiposity were consistently associated with higher VTE risk.

OBJECTIVE. Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass, and fat-free mass in older women and men enrolled in four similar clinical trials. DESIGN. Pooled analyses of data from four double-blinded, randomized controlled trials. PARTICIPANTS. Women (n=295) and men (n=290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months. MEASUREMENTS. 12-month changes in BMD, fat mass, fat-free mass, and serum DHEA sulfate (DHEAS), (17)estradiol, testosterone, and insulin-like growth factor-1 (IGF-1). RESULTS. Women on DHEA had increases (mean±SD; all p

Fracture risk is determined by bone strength and the risk of falls. The relationship between serum sex steroids and bone strength parameters in men is well known, whereas the predictive value of sex steroids for falls is less studied. The aim of this study was to assess the associations between serum testosterone (T) and estradiol (E2) and the likelihood of falls. Older men (aged ≥65 years) from the United States (n = 1919), Sweden (n = 2495), and Hong Kong (n = 1469) participating in the Osteoporotic Fractures in Men Study had baseline T and E2 analyzed by mass spectrometry. Bioavailable (Bio) levels were calculated using mass action equations. Incident falls were ascertained every 4 months during a mean follow‐up of 5.7 years. Associations between sex steroids and falls were estimated by generalized estimating equations. Fall rate was highest in the US and lowest in Hong Kong (US 0.50, Sweden 0.31, Hong Kong 0.12 fall reports/person/year). In the combined cohort of 5883 men, total T (odds ratio [OR] per SD increase = 0.88, 95% confidence interval [CI] 0.86–0.91) and BioT (OR = 0.86, 95% CI 0.83–0.88) were associated with incident falls in models adjusted for age and prevalent falls. These associations were only slightly attenuated after simultaneous adjustment for physical performance variables (total T: OR = 0.94, 95% CI 0.91–0.96; BioT: OR = 0.91, 95% CI 0.89–0.94). E2, BioE2, and sex hormone‐binding globulin (SHBG) were not significantly associated with falls. Analyses in the individual cohorts showed that both total T and BioT were associated with falls in MrOS US and Sweden. No association was found in MrOS Hong Kong, and this may be attributable to environmental factors rather than ethnic differences because total T and BioT predicted falls in MrOS US Asians. In conclusion, low total T and BioT levels, but not E2 or SHBG, are associated with increased falls in older men. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men. © 2016 American Society for Bone and Mineral Research.

BackgroundSerum phosphorus is associated with cardiovascular disease (CVD) in the general population, but may not comprehensively reflect phosphorus homeostasis. Whether urine phosphorus-creatinine ratio (a marker of intestinal absorption) or urine fractional excretion of phosphorus (FEPi; a marker of urinary phosphorus handling) is associated with risk of mortality or CVD is uncertain.Study designProspective observational study.Setting & participants1,325 community-dwelling men 65 years or older participating in the MrOS Study.PredictorSerum phosphorus, urine phosphorus-creatinine ratio, and FEPi.OutcomesAll-cause and CVD death.ResultsMean age was 74 ± 6 (SD) years, estimated glomerular filtration rate was 75 ± 16 mL/min/1.73 m(2), and serum phosphorus level was 3.2 ± 0.4 mg/dL. During a median follow-up of 9.3 years, there were 364 (120 CVD) deaths. After adjustment for demographics, CVD risk factors, and kidney function, the risks of all-cause death in the highest quartiles of serum phosphorus (≥3.6 mg/dL), urine phosphorus-creatinine ratio (≥0.55), and FEPi (≥18%) were 1.63 (95% CI, 1.23-2.17), 1.22 (95% CI, 0.90-1.65), and 0.88 (95% CI, 0.64-1.23), respectively, compared to the lowest quartiles of each. Results were similar for CVD death. Results also were similar in those with estimated glomerular filtration rate ≥60 and

Peripheral conversion of androgens to oestrogens via aromatase is the primary source of oestrogen in postmenopausal women and may play a role in cardiovascular health.Prospective. PARTICIPANTS, MEASUREMENTS: The association of an index of aromatase activity (AROM), the serum oestrone-to-androstenedione ratio, with 25-year cardiovascular disease (CVD) mortality was examined in 819 postmenopausal non-oestrogen using women (mean age at baseline = 72).Overall, 247 deaths were attributed to CVD. The median AROM value was 60 (95% range 17-129). AROM was positively correlated with age (r = 0·28) and body mass index (BMI) (r = 0·22) (P0·001). The age-adjusted risk for CVD mortality was significantly elevated for women in the lowest (HR = 2·01, 95% CI 1·31-3·12) and highest (HR = 1·51, 95%CI 1·02-2·22) quintiles of AROM, compared with the middle quintile. This U-shaped association persisted after additional adjustment for BMI, waist-to-hip ratio, exercise, smoking, alcohol use and traditional CVD risk factor covariates. There was a significant interaction of AROM and BMI (P = 0·001), such that high AROM was associated with a 63% reduction in risk of CVD death for women with low BMI (22 kg/m(2) ), but with 2·1- to 2·5-fold increased risk in women with mid-range (22-25 kg/m(2) ) and high (≥25 kg/m(2) ) BMI. Oestradiol did not influence AROM associations and was not independently related to CVD death.These results suggest that aromatase is a novel endocrine factor predictive of CVD mortality among postmenopausal women. If confirmed, additional studies are needed to determine whether extremes of aromatase reflect genetic influences or underlying disease processes.

ObjectivesThe goal of this study was to evaluate the prospective association of fetuin-A levels with cardiovascular disease (CVD) mortality.BackgroundFetuin-A is a circulating inhibitor of calcium deposition in the vasculature and of insulin action in muscle and fat, and may be involved in the pathogenesis of CVD.MethodsThis is a population-based prospective study of 633 men and 1,025 women (median age = 73 years) who had fetuin-A levels and CVD risk factors evaluated in 1992 to 1996 and were followed for vital status through 2010.ResultsPlasma fetuin-A (g/l ± SD) was highest in women using oral estrogens (0.55 ± 0.12), intermediate for women not using oral estrogens (0.51 ± 0.10), and lowest for men (0.50 ± 0.10), p < 0.001. Lower fetuin-A levels were associated with older age, but with lower levels of other CVD risk factors including adiposity, blood pressure, lipids, triglycerides, and insulin resistance (all p < 0.01). During the median 12-year follow-up, 273 deaths were attributed to CVD. The association of fetuin-A with CVD mortality differed by diabetes status (p for interaction = 0.003). Adjusting for age, sex, oral estrogens, and lifestyle, the hazard ratio for CVD mortality comparing the lowest fetuin-A quartile with all higher values was 1.76 (95% confidence interval [CI]: 1.34 to 2.31; p < 0.001) for participants without diabetes and 0.43 (95% CI: 0.19 to 0.98; p = 0.046) for participants with diabetes.ConclusionsLow fetuin-A levels predicted greater risk for CVD mortality in older adults without diabetes, but were associated with reduced risk of CVD death in those with diabetes. Fetuin-A may provide novel insight into mechanisms leading to CVD death in those with versus without diabetes.

The purpose of this study was to determine the association between neutrophil gelatinase-associated lipocalin (NGAL) levels and cardiovascular and all-cause mortality in community-dwelling older adults.NGAL is a novel marker best known for its role in rapidly identifying acute kidney injury. Although expressed in atherosclerosis, its association with cardiovascular disease (CVD) in the community has not been reported.We measured plasma NGAL levels in 1,393 Rancho Bernardo Study participants without CVD, mean age 70 years. Participants were followed for a mean time period of 11 years.During follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and creatinine clearance, NGAL was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase: 1.33, 95% confidence interval [CI]: 1.12 to 1.57), all-cause mortality (HR: 1.19, 95% CI: 1.07 to 1.32), and a combined cardiovascular endpoint (HR: 1.26, 95% CI: 1.10 to 1.45). After further adjusting for N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), NGAL remained an independent predictor of each outcome. NGAL improved the C-statistic (0.835 to 0.842) for prediction of CVD death (p = 0.001). Net reclassification improvement (0) with the addition of NGAL was 18% (p = 0.02); the integrated discrimination index was also significant (p = 0.01). Participants with NGAL and NT-proBNP above the median had increased risk of CVD death versus those with only NT-proBNP elevated (HR: 1.43, 95% CI: 1.12 to 1.82).Plasma NGAL is a significant predictor of mortality and CVD in community-dwelling older adults, independent of traditional risk factors and kidney function, and adds incremental value to NT-proBNP and CRP. The potential impact of these results includes providing insight into new mechanisms of CVD and the possibility of improving screening, intervention, and prevention.

Postmenopausal women consistently have higher phosphorus levels than similarly aged men. As it is known that estradiol induces phosphaturia in rodents, we evaluated the cross-sectional association of sex hormones with serum phosphorus in 1346 community-living older men (mean age 76) of which 18% had moderate (stage 3) kidney disease. Using linear regression with serum phosphorus levels as the dependent variable, we found that for each 10 pg/ml higher total estradiol level there was a statistically significant 0.05 mg/dl lower serum phosphorus when adjusted for age, ethnicity, testosterone, sex hormone-binding globulin, calcium, estimated glomerular filtration rate, intact parathyroid hormone, 25(OH) vitamin D, bone mineral density, and alkaline phosphatase. These results were similar in individuals with or without chronic kidney disease. Serum testosterone concentrations were also statistically significantly associated with lower serum phosphorus levels. We confirmed these results in an independent sample of 2555 older men, wherein these associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Hence, our study of community-living older men suggests that estradiol may directly or indirectly induce phosphaturia in humans. The mechanism responsible for the association of testosterone with serum phosphorus remains to be determined.

Background Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. Findings Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. Interpretation Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

Despite overwhelming biological plausibility, evidence for a protective effect of oestrogen on cognitive function in postmenopausal women is inconsistent. This study examines the association between endogenous oestrogen levels and subsequent 4-year decline in cognitive function test performance in community-dwelling older women.Longitudinal cohort study.Three hundred and forty-three postmenopausal women (median age 70 years).Between 1984 and 1987, serum for measurement of sex hormones was obtained along with relevant covariates. Cognitive function was assessed in 1988-1991 and again in 1992-1996 using the Category Fluency test, the Mini-Mental Status Exam (MMSE) and Trail Making Test B (Trails B).Women in the highest tertile of oestrone and bioavailable oestradiol had respectively 1.75 (95% CI 1.02, 3.07) and 1.79 (95% CI 1.04, 3.10) higher odds of 4 year decline in Category Fluency, a test of frontal lobe function, compared to those in the lowest tertile, independent of age and education. The 20% of women with highest tertile levels of both oestrone and bioavailable oestradiol had a twofold higher odds of verbal fluency loss (OR = 2.17; 95% CI 1.21, 3.89). Adjustment for testosterone levels or for obesity-related factors associated with high endogenous oestrogens (higher body mass index, waist girth, and triglycerides and lower high-density lipoprotein cholesterol) did not alter results. Neither oestrogen was associated with change in MMSE or Trails B scores.Higher endogenous oestrogen levels were associated with a greater decline in verbal fluency in postmenopausal women. This association was not explained by elevated androgens or by obesity or obesity-related factors.

This study investigated the prognostic value of detectable cardiac troponin T (TnT) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in a population of community-dwelling older adults.Minimally elevated levels of TnT, a marker of cardiomyocyte injury, have been found in small subsets of the general population, with uncertain implications. A marker of ventricular stretch, NT-proBNP has clinical utility in many venues, but its long-term prognostic value in apparently healthy older adults and in conjunction with TnT is unknown.Participants were 957 older adults from the Rancho Bernardo Study with plasma NT-proBNP and TnT measured at baseline (1997 to 1999) and followed up for mortality through July 2006.Participants with detectable TnT (/=0.01 ng/ml, n = 39) had an increased risk of all-cause and cardiovascular death (adjusted hazard ratio [HR] by Cox proportional hazards analysis: 2.06; 95% confidence interval [CI]: 1.29 to 3.28, p = 0.003 for all-cause mortality; HR: 2.06, 95% CI: 1.03 to 4.12, p = 0.040 for cardiovascular mortality); elevated NT-proBNP also predicted an increased risk of all-cause and cardiovascular mortality (adjusted HR per unit-log increase in NT-proBNP: 1.85, 95% CI: 1.36 to 2.52, p0.001 for all-cause mortality; HR: 2.51, 95% CI: 1.55 to 4.08, p0.001 for cardiovascular mortality). Those with both elevated NT-proBNP and detectable TnT had poorer survival (HR for high NT-proBNP and detectable TnT vs. low NT-proBNP and any TnT: 3.20, 95% CI: 1.91 to 5.38, p0.001). Exclusion of the 152 participants with heart disease at baseline did not materially change the TnT mortality or NT-proBNP mortality associations.Apparently healthy adults with detectable TnT or elevated NT-proBNP levels are at increased risk of death. Those with both TnT and NT-proBNP elevations are at even higher risk, and the increased risk persists for years.

ObjectivesThis study investigated the prognostic value of detectable cardiac troponin T (TnT) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in a population of community-dwelling older adults.BackgroundMinimally elevated levels of TnT, a marker of cardiomyocyte injury, have been found in small subsets of the general population, with uncertain implications. A marker of ventricular stretch, NT-proBNP has clinical utility in many venues, but its long-term prognostic value in apparently healthy older adults and in conjunction with TnT is unknown.MethodsParticipants were 957 older adults from the Rancho Bernardo Study with plasma NT-proBNP and TnT measured at baseline (1997 to 1999) and followed up for mortality through July 2006.ResultsParticipants with detectable TnT (≥0.01 ng/ml, n = 39) had an increased risk of all-cause and cardiovascular death (adjusted hazard ratio [HR] by Cox proportional hazards analysis: 2.06; 95% confidence interval [CI]: 1.29 to 3.28, p = 0.003 for all-cause mortality; HR: 2.06, 95% CI: 1.03 to 4.12, p = 0.040 for cardiovascular mortality); elevated NT-proBNP also predicted an increased risk of all-cause and cardiovascular mortality (adjusted HR per unit-log increase in NT-proBNP: 1.85, 95% CI: 1.36 to 2.52, p < 0.001 for all-cause mortality; HR: 2.51, 95% CI: 1.55 to 4.08, p < 0.001 for cardiovascular mortality). Those with both elevated NT-proBNP and detectable TnT had poorer survival (HR for high NT-proBNP and detectable TnT vs. low NT-proBNP and any TnT: 3.20, 95% CI: 1.91 to 5.38, p < 0.001). Exclusion of the 152 participants with heart disease at baseline did not materially change the TnT mortality or NT-proBNP mortality associations.ConclusionsApparently healthy adults with detectable TnT or elevated NT-proBNP levels are at increased risk of death. Those with both TnT and NT-proBNP elevations are at even higher risk, and the increased risk persists for years.

ObjectivesThe aim of this study was to determine the association of fetuin-A with subclinical cardiovascular disease (CVD) in community-living individuals.BackgroundFetuin-A is a hepatic secretory protein that inhibits arterial calcium deposition in vitro. Lower fetuin-A levels are associated with arterial calcification and death in end-stage renal disease populations. The association of fetuin-A with subclinical CVD in the general population is unknown.MethodsAmong 1,375 community-living individuals without prevalent clinical CVD, we measured plasma fetuin-A concentrations. Peripheral arterial disease (PAD) was defined by ankle brachial index 300) with ordinal logistic regression, each SD higher fetuin-A was associated with 31% lower odds of CAC severity (proportional odds ratio: 0.69; 95% confidence interval: 0.46 to 0.92; p = 0.008) in models adjusted for demographic data, lifestyle factors, traditional CVD risk factors, and kidney function. In contrast, no association of fetuin-A was observed with PAD or high common or internal cIMT in adjusted models.ConclusionsLower fetuin-A levels are independently associated with greater CAC severity but not PAD or cIMT. If confirmed, fetuin-A might mark calcium deposition within the vasculature but not atherosclerosis per se.

ObjectivesThe purpose of this study was to determine the association between neutrophil gelatinase–associated lipocalin (NGAL) levels and cardiovascular and all-cause mortality in community-dwelling older adults.BackgroundNGAL is a novel marker best known for its role in rapidly identifying acute kidney injury. Although expressed in atherosclerosis, its association with cardiovascular disease (CVD) in the community has not been reported.MethodsWe measured plasma NGAL levels in 1,393 Rancho Bernardo Study participants without CVD, mean age 70 years. Participants were followed for a mean time period of 11 years.ResultsDuring follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and creatinine clearance, NGAL was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase: 1.33, 95% confidence interval [CI]: 1.12 to 1.57), all-cause mortality (HR: 1.19, 95% CI: 1.07 to 1.32), and a combined cardiovascular endpoint (HR: 1.26, 95% CI: 1.10 to 1.45). After further adjusting for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP), NGAL remained an independent predictor of each outcome. NGAL improved the C-statistic (0.835 to 0.842) for prediction of CVD death (p = 0.001). Net reclassification improvement (>0) with the addition of NGAL was 18% (p = 0.02); the integrated discrimination index was also significant (p = 0.01). Participants with NGAL and NT-proBNP above the median had increased risk of CVD death versus those with only NT-proBNP elevated (HR: 1.43, 95% CI: 1.12 to 1.82).ConclusionsPlasma NGAL is a significant predictor of mortality and CVD in community-dwelling older adults, independent of traditional risk factors and kidney function, and adds incremental value to NT-proBNP and CRP. The potential impact of these results includes providing insight into new mechanisms of CVD and the possibility of improving screening, intervention, and prevention.

ObjectivesLipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident coronary heart disease (CHD) in adults without known CHD, independent of heart disease risk factors. We examined whether the independent association was apparent in older adults.BackgroundSerum levels of Lp-PLA2, an enzyme that hydrolyzes oxidized phospholipids to yield potentially proatherogenic particles, have been associated with CHD and may help predict cardiovascular risk.MethodsParticipants were 1,077 community-dwelling men and women, median age 72 years, who had no known CHD at baseline (1984 to 1987) when blood samples and risk factor data were collected. Participants were followed for CHD events for a mean of 16 years, through 2002. Cox proportional hazards regression models were used to examine the association of serum Lp-PLA2 with incident CHD (myocardial infarction, angina, or coronary revascularization).ResultsThe Lp-PLA2 levels positively correlated with age (r = 0.09), body mass index (r = 0.11), low-density lipoprotein (r = 0.37), triglycerides (r = 0.25), and C-reactive protein (r = 0.10), and negatively correlated with high-density lipoprotein (r = −0.27) (all p < 0.05). During follow-up, 228 participants had incident CHD events. Lipoprotein-associated phospholipase A2 levels in the second, third, and fourth quartiles predicted an increased risk of CHD compared with the lowest quartile (hazard ratios 1.66, 1.80, and 1.89, respectively; p < 0.05 for each). This association persisted after adjusting for C-reactive protein and other CHD risk factors.ConclusionsElevated Lp-PLA2 levels predict CHD events in apparently healthy older adults, independent of CHD risk factors.