03296nas a2200409 4500008004100000022001400041245013600055210006900191260001300260300001300273490000700286520212000293653005102413653000902464653002202473653002802495653003002523653001102553653001102564653001402575653002302589653000902612653001602621653003002637653001502667653002402682653000902706653001702715100001702732700001602749700001602765700001502781700001902796700001702815700001802832856003602850 2012 eng d a1945-719700aLipoprotein-associated phospholipase A2 (Lp-PLA2) and future risk of type 2 diabetes: results from the Cardiovascular Health Study.0 aLipoproteinassociated phospholipase A2 LpPLA2 and future risk of c2012 May a1695-7010 v973 a

INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) has been consistently associated with cardiovascular disease (CVD) risk factors and predictive of CVD outcomes; furthermore, it is consistently higher among type 2 diabetics than nondiabetics. However, the relationships of circulating Lp-PLA(2) mass and activity with incident type 2 diabetes mellitus have not been examined. Therefore, the purpose of this study was to determine the association of Lp-PLA(2) mass and activity with type 2 diabetes among older adults.

METHODS: We conducted analyses of Lp-PLA(2) and prevalent and incident diabetes among 5474 men and women from the Cardiovascular Health Study (1989-2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Diabetes status was ascertained annually with medication inventories and repeated blood glucose measurements. Generalized linear and Cox proportional hazards models were used to adjust for confounding factors including body mass index and inflammation.

RESULTS: At baseline, the top two quintiles of Lp-PLA(2) activity were significantly associated with prevalent type 2 diabetes with a multivariable relative risk = 1.35 [95% confidence interval (CI) = 1.11-1.63] for quintile 4, and relative risk = 1.33 (95% CI = 1.07-1.66) for quintile 5. Among participants free of diabetes at baseline, we found a significant positive association with both the homeostatic model assessment for insulin resistance and β-cell function per SD increase in Lp-PLA(2) activity (P values for both <0.01). In prospective analyses, the risk of incident type 2 diabetes was significantly higher among those in the highest quintile of Lp-PLA(2) activity [multivariable hazard ratio = 1.45 (95% CI = 1.01-2.07)] compared with the lowest quintile. Lp-PLA(2) mass was not significantly associated with incident type 2 diabetes.

DISCUSSION: Lp-PLA(2) activity is positively associated with insulin resistance and predicts incident type 2 diabetes among older adults independent of multiple factors associated with diabetes pathogenesis.

10a1-Alkyl-2-acetylglycerophosphocholine Esterase10aAged10aAged, 80 and over10aCardiovascular Diseases10aDiabetes Mellitus, Type 210aFemale10aHumans10aIncidence10aInsulin Resistance10aMale10aMiddle Aged10aPredictive Value of Tests10aPrevalence10aProspective Studies10aRisk10aRisk Factors1 aNelson, T, L1 aBiggs, M, L1 aKizer, J, R1 aCushman, M1 aHokanson, J, E1 aFurberg, C D1 aMukamal, K, J uhttps://chs-nhlbi.org/node/136903114nas a2200433 4500008004100000022001400041245009600055210006900151260001300220300001100233490000700244520194700251653000902198653002202207653002002229653001502249653001902264653002802283653003502311653002102346653002202367653001102389653001102400653000902411653002602420653002402446653001702470653001102487100001802498700001602516700001602532700001302548700001402561700002002575700001702595700001502612700001702627856003602644 2013 eng d a1432-042800aPrediction and classification of cardiovascular disease risk in older adults with diabetes.0 aPrediction and classification of cardiovascular disease risk in  c2013 Feb a275-830 v563 a

AIMS/HYPOTHESIS: We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis.

METHODS: As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged ≥65 years, we examined the 10 year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7 years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred.

RESULTS: The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol, creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle-brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima-media thickness modestly improved discrimination (C statistic 0.68; p = 0.002) and classification (net reclassification improvement [NRI] 0.12; p = 0.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures.

CONCLUSIONS/INTERPRETATION: Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better understanding of the pathophysiology and determinants of CVD in this patient group is needed.

10aAged10aAged, 80 and over10aAtherosclerosis10aBiomarkers10aBlood Pressure10aCardiovascular Diseases10aCarotid Intima-Media Thickness10aCholesterol, HDL10aDiabetes Mellitus10aFemale10aHumans10aMale10aMyocardial Infarction10aRegression Analysis10aRisk Factors10aStroke1 aMukamal, K, J1 aKizer, J, R1 aDjoussé, L1 aIx, J, H1 aZieman, S1 aSiscovick, D, S1 aSibley, C, T1 aTracy, R P1 aArnold, A, M uhttps://chs-nhlbi.org/node/585902511nas a2200229 4500008004100000022001400041245011600055210006900171260001600240520182000256100001802076700001802094700001702112700001602129700002002145700001602165700001602181700001602197700001702213700001502230856003602245 2016 eng d a1590-372900aThe association of lean and fat mass with all-cause mortality in older adults: The Cardiovascular Health Study.0 aassociation of lean and fat mass with allcause mortality in olde c2016 Jun 283 a

BACKGROUND AND AIMS: Understanding contributions of lean and fat tissue to cardiovascular and non-cardiovascular mortality may help clarify areas of prevention in older adults. We aimed to define distributions of lean and fat tissue in older adults and their contributions to cause-specific mortality.

METHODS AND RESULTS: A total of 1335 participants of the Cardiovascular Health Study (CHS) who underwent dual-energy x-ray absorptiometry (DEXA) scans were included. We used principal components analysis (PCA) to define two independent sources of variation in DEXA-derived body composition, corresponding to principal components composed of lean ("lean PC") and fat ("fat PC") tissue. We used Cox proportional hazards regression using these PCs to investigate the relationship between body composition with cardiovascular and non-cardiovascular mortality. Mean age was 76.2 ± 4.8 years (56% women) with mean body mass index 27.1 ± 4.4 kg/m(2). A greater lean PC was associated with lower all-cause (HR = 0.91, 95% CI 0.84-0.98, P = 0.01) and cardiovascular mortality (HR = 0.84, 95% CI 0.74-0.95, P = 0.005). The lowest quartile of the fat PC (least adiposity) was associated with a greater hazard of all-cause mortality (HR = 1.24, 95% CI 1.04-1.48, P = 0.02) relative to fat PCs between the 25th-75th percentile, but the highest quartile did not have a significantly greater hazard (P = 0.70).

CONCLUSION: Greater lean tissue mass is associated with improved cardiovascular and overall mortality in the elderly. The lowest levels of fat tissue mass are linked with adverse prognosis, but the highest levels show no significant mortality protection. Prevention efforts in the elderly frail may be best targeted toward improvements in lean muscle mass.

1 aSpahillari, A1 aMukamal, K, J1 aDeFilippi, C1 aKizer, J, R1 aGottdiener, J S1 aDjoussé, L1 aLyles, M, F1 aBartz, T, M1 aMurthy, V, L1 aShah, R, V uhttps://chs-nhlbi.org/node/713402836nas a2200277 4500008004100000022001400041245007000055210006900125260001600194520207400210100001102284700001602295700001602311700002002327700001802347700001702365700001802382700001502400700002002415700001602435700001802451700001502469700002002484700001802504856003602522 2016 eng d a1464-549100aBrain natriuretic peptide and insulin resistance in older adults.0 aBrain natriuretic peptide and insulin resistance in older adults c2016 Apr 213 a

AIMS: Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established.

METHODS: N-Terminal (NT)-proBNP was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance.

RESULTS: Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P < 0.001 for all four indices). Although the genetic score was strongly related to measured NT-proBNP levels amongst European Americans (F statistic = 71.08), we observed no association of genetically determined NT-proBNP with insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP).

CONCLUSIONS: In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. This article is protected by copyright. All rights reserved.

1 aKim, F1 aBiggs, M, L1 aKizer, J, R1 aBrutsaert, E, F1 ade Fillipi, C1 aNewman, A, B1 aKronmal, R, A1 aTracy, R P1 aGottdiener, J S1 aDjoussé, L1 ade Boer, I, H1 aPsaty, B M1 aSiscovick, D, S1 aMukamal, K, J uhttps://chs-nhlbi.org/node/712402719nas a2200241 4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520205900230100001902289700001802308700001602326700001602342700001302358700001502371700002002386700001702406700001802423856003602441 2016 eng d a1433-296500aFibrosis markers, hip fracture risk, and bone density in older adults.0 aFibrosis markers hip fracture risk and bone density in older adu c2016 Feb a815-200 v273 a

UNLABELLED: We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-β1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-β1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome.

INTRODUCTION: TGF-β1 serves several roles in bone formation and resorption. A consequence of TGF-β1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels.

METHODS: Participants were from the Cardiovascular Health Study (mean age 78 years; mean follow-up 8.3 years). We included 1681 persons with measured levels of TGF-β1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures).

RESULTS: Among women, higher TGF-β1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95 % CI 0.61, 0.91]). Among men, TGF-β1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-β1 on fracture risk). TGF-β1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women.

CONCLUSIONS: TGF-β1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-β1 levels and hip fracture risk and bone density require further investigation.

1 aBarzilay, J, I1 aBůžková, P1 aKizer, J, R1 aDjoussé, L1 aIx, J, H1 aFink, H, A1 aSiscovick, D, S1 aCauley, J, A1 aMukamal, K, J uhttps://chs-nhlbi.org/node/680602189nas a2200181 4500008004100000022001400041245014000055210006900195260001600264520159400280100001501874700001601889700001401905700001601919700001801935700001801953856003601971 2018 eng d a1590-372900aFasting and post-glucose load measures of insulin resistance and risk of incident atrial fibrillation: The Cardiovascular Health Study.0 aFasting and postglucose load measures of insulin resistance and  c2018 Mar 023 a

BACKGROUND AND AIMS: Existing literature in individuals without diabetes has not demonstrated a relationship between IR and incident AF; however, data are limited and only fasting glucose measures of IR were assessed. We evaluated the relationship of both fasting and post-glucose load IR measures with the development of atrial fibrillation in nondiabetic older adults.

METHODS AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), those without prevalent AF or diabetes and with IR measures at baseline were followed for the development of AF, identified by follow-up visit electrocardiograms, hospital discharge diagnosis coding, or Medicare claims data, through 2014. Fasting IR was determined by the homeostatic model of insulin resistance (HOMA-IR) and post-glucose load IR was determined by the Gutt index. Cox proportional hazards models were used to determine the association of IR with risk of AF. Analyses included 3601 participants (41% men) with a mean age of 73 years. Over a median follow-up of 12.3 years, 1443 (40%) developed AF. After multivariate adjustment, neither HOMA-IR nor the Gutt index was associated with risk of developing AF [hazard ratios (95% confidence intervals): 0.96 (0.90, 1.03) for 1-SD increase in HOMA-IR and 1.03 (0.97, 1.10) for 1-SD decrease in the Gutt index].

CONCLUSIONS: We found no evidence of an association between either fasting or post-glucose load IR measures and incident AF.

1 aGarg, P, K1 aBiggs, M, L1 aKaplan, R1 aKizer, J, R1 aHeckbert, S R1 aMukamal, K, J uhttps://chs-nhlbi.org/node/766602781nas a2200253 4500008004100000022001400041245012400055210006900179260001600248520203400264100001502298700001002313700001702323700002402340700001802364700001302382700002002395700001502415700001802430700001602448700001102464700001602475856003602491 2019 eng d a1433-296500aBiochemical markers of bone turnover and risk of incident hip fracture in older women: the Cardiovascular Health Study.0 aBiochemical markers of bone turnover and risk of incident hip fr c2019 Jun 213 a

The relationships of osteocalcin (OC) and C-telopeptide of type I collagen (CTX) with long-term incidence of hip fracture were examined in 1680 post-menopausal women from a population-based study. CTX, but not OC, levels were associated with incident hip fracture in these participants, a relationship characterized by an inverted U-shape.

INTRODUCTION: We sought to investigate the relationships of OC, a marker of bone formation, and CTX, a marker of bone resorption, with long-term incidence of hip fracture in older women.

METHODS: We included 1680 women from the population-based Cardiovascular Health Study (mean [SD] age 74.5 [5.0] years). The longitudinal association of both markers with incidence of hip fracture was examined using multivariable Cox models.

RESULTS: During a median follow-up of 12.3 years, 288 incident hip fractures occurred. Linear spline analysis did not demonstrate an association between OC levels and incident hip fracture. By contrast, increasing levels of CTX up to the middle-upper range were associated with a significantly greater risk of hip fracture (HR = 1.52 per SD increment, 95% CI = 1.10-2.09), while further increases were associated with a marginally non-significant lower risk (HR = 0.80 per SD increment, 95% CI = 0.63-1.01), after full adjustment for potential confounders. In analyses of quartiles, CTX exhibited a similar inverted U-shaped relationship with incident fracture after adjustment, with a significant association observed only for the comparison of quartile 3 to quartile 1 (HR = 1.63, 95% CI = 1.10-2.43). In a subset with available measures, both OC and CTX were inversely associated with bone mineral density of the hip.

CONCLUSION: CTX, but not OC, levels were associated with incident hip fracture in post-menopausal women, a relationship characterized by an inverted U-shape. These findings highlight the complex relationship of bone turnover markers with hip fracture risk.

1 aMassera, D1 aXu, S1 aWalker, M, D1 aValderrábano, R, J1 aMukamal, K, J1 aIx, J, H1 aSiscovick, D, S1 aTracy, R P1 aRobbins, J, A1 aBiggs, M, L1 aXue, X1 aKizer, J, R uhttps://chs-nhlbi.org/node/8106