03263nas a2200553 4500008004100000022001400041245011200055210006900167260001300236300001100249490000600260520171300266653000901979653002201988653003402010653002102044653001102065653003402076653001102110653000902121653001602130653003602146653002402182100002302206700001602229700002102245700002002266700001902286700001202305700002102317700002302338700002102361700002102382700001602403700001902419700001802438700002302456700001902479700002202498700001702520700001902537700001902556700002102575700001702596700002402613700001702637700001902654856003602673 2011 eng d a1942-326800aAssociation of genetic variants and incident coronary heart disease in multiethnic cohorts: the PAGE study.0 aAssociation of genetic variants and incident coronary heart dise c2011 Dec a661-720 v43 a

BACKGROUND: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.

METHODS AND RESULTS: The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.

CONCLUSIONS: Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.

10aAged10aAged, 80 and over10aContinental Population Groups10aCoronary Disease10aFemale10aGenome-Wide Association Study10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aProspective Studies1 aFranceschini, Nora1 aCarty, Cara1 aBůzková, Petra1 aReiner, Alex, P1 aGarrett, Tiana1 aLin, Yi1 aVöckler, Jens-S1 aHindorff, Lucia, A1 aCole, Shelley, A1 aBoerwinkle, Eric1 aLin, Dan-Yu1 aBookman, Ebony1 aBest, Lyle, G1 aBella, Jonathan, N1 aEaton, Charles1 aGreenland, Philip1 aJenny, Nancy1 aNorth, Kari, E1 aTaverna, Darin1 aYoung, Alicia, M1 aDeelman, Ewa1 aKooperberg, Charles1 aPsaty, Bruce1 aHeiss, Gerardo uhttps://chs-nhlbi.org/node/134703420nas a2200517 4500008004100000022001400041245023700055210006900292260001600361300001000377490000600387520182700393653000902220653002202229653002802251653002102279653002102300653004002321653001102361653002502372653003402397653001302431653001102444653000902455653001602464653003602480653001702516653001102533653001802544100001902562700002102581700002002602700002302622700001802645700001902663700002302682700002302705700001402728700002002742700001602762700002002778700001902798700002502817700002402842856003602866 2012 eng d a1942-326800aAssociations between incident ischemic stroke events and stroke and cardiovascular disease-related genome-wide association studies single nucleotide polymorphisms in the Population Architecture Using Genomics and Epidemiology study.0 aAssociations between incident ischemic stroke events and stroke  c2012 Apr 01 a210-60 v53 a

BACKGROUND: Genome-wide association studies (GWAS) have identified loci associated with ischemic stroke (IS) and cardiovascular disease (CVD) in European-descent individuals, but their replication in different populations has been largely unexplored.

METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) selected from GWAS and meta-analyses of stroke, and 86 SNPs previously associated with myocardial infarction and CVD risk factors, including blood lipids (high density lipoprotein [HDL], low density lipoprotein [LDL], and triglycerides), type 2 diabetes, and body mass index (BMI), were investigated for associations with incident IS in European Americans (EA) N=26 276, African-Americans (AA) N=8970, and American Indians (AI) N=3570 from the Population Architecture using Genomics and Epidemiology Study. Ancestry-specific fixed effects meta-analysis with inverse variance weighting was used to combine study-specific log hazard ratios from Cox proportional hazards models. Two of 9 stroke SNPs (rs783396 and rs1804689) were significantly associated with [corrected] IS hazard in AA; none were significant in this large EA cohort. Of 73 CVD risk factor SNPs tested in EA, 2 (HDL and triglycerides SNPs) were associated with IS. In AA, SNPs associated with LDL, HDL, and BMI were significantly associated with IS (3 of 86 SNPs tested). Out of 58 SNPs tested in AI, 1 LDL SNP was significantly associated with IS.

CONCLUSIONS: Our analyses showing lack of replication in spite of reasonable power for many stroke SNPs and differing results by ancestry highlight the need to follow up on GWAS findings and conduct genetic association studies in diverse populations. We found modest IS associations with BMI and lipids SNPs, though these findings require confirmation.

10aAged10aAged, 80 and over10aCardiovascular Diseases10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aFemale10aGenetics, Population10aGenome-Wide Association Study10aGenomics10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk Factors10aStroke10aTriglycerides1 aCarty, Cara, L1 aBůzková, Petra1 aFornage, Myriam1 aFranceschini, Nora1 aCole, Shelley1 aHeiss, Gerardo1 aHindorff, Lucia, A1 aHoward, Barbara, V1 aMann, Sue1 aMartin, Lisa, W1 aZhang, Ying1 aMatise, Tara, C1 aPrentice, Ross1 aReiner, Alexander, P1 aKooperberg, Charles uhttps://chs-nhlbi.org/node/137103502nas a2200481 4500008004100000022001400041245014100055210006900196260001600265300001000281490000800291520213900299653000902438653002402447653002802471653002702499653001502526653001802541653001102559653001102570653001402581653000902595653001602604653003202620653002002652653001702672653001602689653001802705100001702723700002202740700002102762700001902783700001802802700002302820700002002843700002402863700001902887700001702906700002102923700002102944700001902965856003602984 2013 eng d a2168-611400aAtrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study.0 aAtrial fibrillation and the risk of sudden cardiac death the ath c2013 Jan 14 a29-350 v1733 a

BACKGROUND: It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.

METHODS: In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.

RESULTS: In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.

CONCLUSIONS: Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.

10aAged10aAtrial Fibrillation10aCardiovascular Diseases10aDeath, Sudden, Cardiac10aDemography10aEthnic Groups10aFemale10aHumans10aIncidence10aMale10aMiddle Aged10aProportional Hazards Models10aRisk Assessment10aRisk Factors10aSex Factors10aUnited States1 aChen, Lin, Y1 aSotoodehnia, Nona1 aBůzková, Petra1 aLopez, Faye, L1 aYee, Laura, M1 aHeckbert, Susan, R1 aPrineas, Ronald1 aSoliman, Elsayed, Z1 aAdabag, Selcuk1 aKonety, Suma1 aFolsom, Aaron, R1 aSiscovick, David1 aAlonso, Alvaro uhttps://chs-nhlbi.org/node/585003001nas a2200397 4500008004100000022001400041245012100055210006900176260001300245300001300258490000700271520187200278653001002150653000902160653002202169653002802191653001702219653002802236653001102264653002202275653002002297653001102317653001402328653000902342653002302351100002002374700002102394700002502415700002402440700002002464700002002484700002402504700002002528700001902548856003602567 2015 eng d a1523-468100aAssociation of Fetuin-A With Incident Fractures in Community-Dwelling Older Adults: The Cardiovascular Health Study.0 aAssociation of FetuinA With Incident Fractures in CommunityDwell c2015 Aug a1394-4020 v303 a

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.

10aAdult10aAged10aAged, 80 and over10aalpha-2-HS-Glycoprotein10aBone Density10aCross-Sectional Studies10aFemale10aFollow-Up Studies10aFractures, Bone10aHumans10aIncidence10aMale10aModels, Biological1 aFink, Howard, A1 aBůzková, Petra1 aGarimella, Pranav, S1 aMukamal, Kenneth, J1 aCauley, Jane, A1 aKizer, Jorge, R1 aBarzilay, Joshua, I1 aJalal, Diana, I1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/666602547nas a2200229 4500008004100000022001400041245016500055210006900220260001300289300000900302490000700311520179200318100002502110700002702135700002102162700001402183700001702197700002002214700002502234700002202259856003602281 2016 eng d a1532-223800aAgreement between circulating IGF-I, IGFBP-1 and IGFBP-3 levels measured by current assays versus unavailable assays previously used in epidemiological studies.0 aAgreement between circulating IGFI IGFBP1 and IGFBP3 levels meas c2016 Feb a11-60 v263 a

OBJECTIVE: Levels of insulin-like growth factor (IGF) proteins are associated with the risk of cancer and mortality. IGF assays produced by Diagnostic Systems Laboratories (DSL) were widely used in epidemiological studies, were not calibrated against recommended standards and are no longer commercially available.

DESIGN: In a split sample study among 1471 adults participating in the Cardiovascular Health Study, we compared values obtained using DSL assays with alternative assays for serum IGF-I (Immunodiagnostic Systems, IDS), IGFBP-1 (American Laboratory Products Company, ALPCO) and IGFBP-3 (IDS).

RESULTS: Results were compared using kernel density estimation plots, quartile analysis with weighted kappa statistics and linear regression models to assess the concordance of data from the different assays. Participants had a mean age of 77years. Results between alternative assays were strongly correlated (IGF-I, r=0.93 for DSL versus IDS; log-IGFBP-1, r=0.90 for DSL versus ALPCO; IGFBP-3, r=0.92 for DSL versus IDS). Cross tabulations showed that participants were usually in the same quartile categories regardless of the assay used (overall agreement, 74% for IGF-I, 64% for IGFBP-1, 71% for IGFBP-3). Weighted kappa also showed substantial agreement between assays (kw, 0.78 for IGF-I, 0.69 for IGFBP-1, 0.76 for IGFBP-3). Regressions of levels obtained with DSL assays (denoted X) to alternative assays were, IGF-I: 0.52X+15.2ng/ml, log-IGFBP-1: 1.01X-1.73ng/ml IGFBP-3: 0.87X+791.1ng/ml. Serum values of IGF-I, IGFBP-1 and IGFBP-3 measured using alternative assays are moderately correlated.

CONCLUSIONS: Care is needed in the interpretation of data sets involving IGF analytes if assay methodologies are not uniform.

1 aAneke-Nash, Chino, S1 aDominguez-Islas, Clara1 aBůzková, Petra1 aQi, Qibin1 aXue, XiaoNan1 aPollak, Michael1 aStrickler, Howard, D1 aKaplan, Robert, C uhttps://chs-nhlbi.org/node/695201955nas a2200217 4500008004100000022001400041245014500055210006900200260001300269300001200282490000800294520125300302100002201555700002101577700002001598700002101618700002001639700002101659700002101680856003601701 2017 eng d a1432-082700aAssociation of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study.0 aAssociation of Plasma SDF1 with Bone Mineral Density Body Compos c2017 Jun a599-6080 v1003 a

Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.

1 aCarbone, Laura, D1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBethel, Monique1 aHamrick, Mark, W1 aHill, William, D uhttps://chs-nhlbi.org/node/734103363nas a2200241 4500008004100000022001400041245014100055210006900196260001600265300001200281490000800293520258100301100003002882700002102912700001802933700001902951700002002970700002102990700002103011700001503032710003803047856003603085 2018 eng d a1873-276300aAssociation of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study.0 aAssociation of bone mineral density with hemoglobin and change i c2018 Nov 15 a321-3260 v1203 a

PURPOSE: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD).

METHODS: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use.

RESULTS: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10 g/cmper 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10 g/cmper 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10 g/cmper 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women.

CONCLUSIONS: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement.

1 aValderrábano, Rodrigo, J1 aBůzková, Petra1 aChang, Po-Yin1 aZakai, Neil, A1 aFink, Howard, A1 aRobbins, John, A1 aLee, Jennifer, S1 aWu, Joy, Y1 aCardiovascular Health Study group uhttps://chs-nhlbi.org/node/793002502nas a2200241 4500008004100000245014200041210006900183260001200252300000900264490000700273520173500280653002502015653001702040653000902057653003202066100001702098700002102115700001702136700002002153700002002173700001802193856004902211 2018 eng d00aThe associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults.0 aassociations of subclinical atherosclerotic cardiovascular disea c08/2018 a22300 v293 aIn the absence of clinically recognized cardiovascular disease, increased carotid artery intimal medial thickness was associated with higher hip fracture risk in older adults, despite its association with higher bone mineral density (BMD). Low ankle brachial index and aortic wall thickness were not associated with fracture risk or BMD. INTRODUCTION: Clinically recognized cardiovascular disease (CVD) is associated with osteoporosis and hip fracture risk, but the relationship of subclinical atherosclerosis to bone health is not certain. METHODS: We followed 3385 participants from the Cardiovascular Health Study (mean age 74.7 ± 5.3 years) with a median time to fracture of 12.1 years who underwent baseline carotid artery and aortic wall ultrasound scanning and ankle brachial blood pressure index (ABI) determinations. A subset underwent bone mineral density (BMD) testing. RESULTS: There were 494 hip fractures during follow-up. Among persons without clinical CVD, an average standard-deviation increase in a composite score of maximal common and internal carotid artery intimal medial thickness (cIMT) was associated with increased risk of hip fracture [(HR 1.18 [1.04, 1.35]), even though cIMT was positively associated with BMD. Neither aortic wall thickness nor ABI were associated with hip fracture risk or BMD. Among participants with clinical CVD, cIMT and aortic wall thickness, but not ABI, were associated with increased hip fracture risk. CONCLUSION: Subclinical cIMT is associated with an increased risk of hip fractures despite being associated with increased BMD. This finding suggests that vascular health, even in its early stages, is linked to bone health, by pathways other than BMD.10aBone mineral density10aHip fracture10aRisk10aSubclinical atherosclerosis1 aBarzilay, JI1 aBůzková, Petra1 aCauley, J, A1 aRobbins, J., A.1 aFink, Howard, A1 aMukamal, K, J uhttps://www.ncbi.nlm.nih.gov/pubmed/3013202703015nas a2200241 4500008004100000022001400041245013700055210006900192260001300261300001200274490000800286520225700294100001402551700002102565700002102586700002002607700002002627700002202647700002202669700002402691700002202715856003602737 2019 eng d a1432-082700aThe Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.0 aAssociation of Aromatic Amino Acids with Incident Hip Fracture a c2019 Aug a161-1720 v1053 a

In 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (n = 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p ≤ 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.

1 aLe, Brian1 aBůzková, Petra1 aRobbins, John, A1 aFink, Howard, A1 aRaiford, Mattie1 aIsales, Carlos, M1 aShikany, James, M1 aCoughlin, Steven, S1 aCarbone, Laura, D uhttps://chs-nhlbi.org/node/810402689nas a2200217 4500008004100000022001400041245012900055210006900184260001600253520198000269100002202249700002102271700002002292700002002312700001402332700002202346700002202368700002402390700002102414856003602435 2019 eng d a1523-468100aAssociation of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study.0 aAssociation of Dietary Niacin Intake With Incident Hip Fracture  c2019 Jan 193 a

Interest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women ≥65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95% CI, 1.04 to 1.66) and highest (HR 1.53; 95% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. © 2018 American Society for Bone and Mineral Research.

1 aCarbone, Laura, D1 aBůzková, Petra1 aFink, Howard, A1 aRaiford, Mattie1 aLe, Brian1 aIsales, Carlos, M1 aShikany, James, M1 aCoughlin, Steven, S1 aRobbins, John, A uhttps://chs-nhlbi.org/node/796702544nas a2200229 4500008004100000022001400041245011800055210006900173260001600242520180400258100002002062700002102082700001902103700002202122700002402144700002302168700002402191700001802215700002002233700002502253856003602278 2019 eng d a1440-179700aAssociation of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study.0 aAssociation of serum and urinary uromodulin and their correlates c2019 Dec 173 a

Uromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (β = 1.3 [1.1-1.6]), log2 C-reactive protein (β = -4.2 [-6.8 to -1.6]) and male sex (β = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (β = 3700 [400-7000]), while diabetes (β = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.

1 aSteubl, Dominik1 aBůzková, Petra1 aIx, Joachim, H1 aDevarajan, Prasad1 aBennett, Michael, R1 aChaves, Paolo, H M1 aShlipak, Michael, G1 aBansal, Nisha1 aSarnak, Mark, J1 aGarimella, Pranav, S uhttps://chs-nhlbi.org/node/827902803nas a2200229 4500008004100000022001400041245012600055210006900181260001600250520205500266100002002321700002102341700002502362700001902387700002202406700002402428700002302452700002402475700001802499700002002517856003602537 2019 eng d a1460-238500aAssociation of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study.0 aAssociation of serum uromodulin with mortality and cardiovascula c2019 Mar 213 a

BACKGROUND: Uromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults.

METHODS: We measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL.

RESULTS: The mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)].

CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.

1 aSteubl, Dominik1 aBůzková, Petra1 aGarimella, Pranav, S1 aIx, Joachim, H1 aDevarajan, Prasad1 aBennett, Michael, R1 aChaves, Paulo, H M1 aShlipak, Michael, G1 aBansal, Nisha1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/800702027nas a2200217 4500008004100000022001400041245012700055210006900182260001500251300001600266490000700282520132500289100002301614700002101637700002401658700003001682700002101712700002001733700002001753856003601773 2020 eng d a1945-458900aAssociation of skeletal muscle mass, kidney disease and mortality in older men and women: the cardiovascular health study.0 aAssociation of skeletal muscle mass kidney disease and mortality c2020 11 02 a21023-210360 v123 a

Low muscle mass (sarcopenia) is a prevalent and major concern in the aging population as well as in patients with chronic kidney disease (CKD). We hypothesized that sarcopenia is an independent predictor of incident and progressive CKD and increased mortality in older men and women (≥65 years) from the Cardiovascular Health Study. Sarcopenia was defined by bioimpedance-estimated skeletal muscle mass index (SMI) as a continuous variable and categorically (normal, class I, and class II). Cox regression hazard ratios (HRs) estimated the risk of incident and prevalent CKD and mortality in individuals with and without CKD. Low SMI was associated with increased prevalence of CKD in men (p<0.001), but lower prevalence of CKD in women (p=0.03). Low muscle mass was not associated with incident CKD or rapid CKD progression (>3 ml/minute/1.73m/year decline in eGFR) in men, but was associated with lower risk of incident CKD in women ([adjusted RR=0.69, 95% (0.51,0.94)]. Low muscle mass (class II) was independently associated with higher mortality only in men [(adjusted HR=1.26, 95% (1.05,1.50)]. Neither definition of sarcopenia was associated with mortality in men or women with CKD. Further studies are needed to understand the mechanisms by which sarcopenia contributes to higher mortality in aging men.

1 aKruse, Nicholas, T1 aBůzková, Petra1 aBarzilay, Joshua, I1 aValderrábano, Rodrigo, J1 aRobbins, John, A1 aFink, Howard, A1 aJalal, Diana, I uhttps://chs-nhlbi.org/node/862702582nas a2200241 4500008004100000022001400041245017200055210006900227260001600296300001200312490000700324520177900331100001902110700002102129700002302150700001802173700002202191700002002213700002002233700002402253700002702277856003602304 2021 eng d a2047-998000aAssociations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort.0 aAssociations of Serum Nonesterified Fatty Acids With Coronary He c2021 Mar 16 ae0191350 v103 a

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.

1 aHuang, Neil, K1 aBůzková, Petra1 aMatthan, Nirupa, R1 aDjoussé, Luc1 aHirsch, Calvin, H1 aKizer, Jorge, R1 aLongstreth, W T1 aMukamal, Kenneth, J1 aLichtenstein, Alice, H uhttps://chs-nhlbi.org/node/870702915nas a2200241 4500008004100000022001400041245022000055210006900275260001600344520204900360100001802409700002402427700002102451700002002472700002102492700002102513700002702534700001902561700002002580700002002600700001702620856003602637 2022 eng d a1097-679500aThe 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.0 aassociation of aortic valve sclerosis aortic annulus increased r c2022 Sep 093 a

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.

1 aBarasch, Eddy1 aGottdiener, John, S1 aTressel, William1 aBartz, Traci, M1 aBůzková, Petra1 aMassera, Daniele1 aDeFilippi, Christopher1 aBiggs, Mary, L1 aPsaty, Bruce, M1 aKizer, Jorge, R1 aOwens, David uhttps://chs-nhlbi.org/node/915402657nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520177800240100001702018700002402035700002302059700002202082700002102104700002002125700002002145700001902165700002202184700002002206700002302226700002002249700002202269700001702291700002302308856003602331 2022 eng d a2055-582200aAssociation of immune cell subsets with incident heart failure in two population-based cohorts.0 aAssociation of immune cell subsets with incident heart failure i c2022 Sep 123 a

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 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 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.

1 aSinha, Arjun1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aFohner, Alison, E1 aBůzková, Petra1 aFloyd, James, S1 aHuber, Sally, A1 aOlson, Nels, C1 aNjoroge, Joyce, N1 aKizer, Jorge, R1 aDelaney, Joseph, A1 aShah, Sanjiv, S1 aTracy, Russell, P1 aPsaty, Bruce1 aFeinstein, Matthew uhttps://chs-nhlbi.org/node/917502302nas a2200229 4500008004100000022001400041245010300055210006900158260001600227520158200243100002401825700002101849700002101870700002001891700002001911700001801931700002101949700002201970700002001992700002402012856003602036 2022 eng d a1555-716200aThe Association of Lipids and Lipoproteins with Hip Fracture Risk the Cardiovascular Health Study.0 aAssociation of Lipids and Lipoproteins with Hip Fracture Risk th c2022 Jun 063 a

BACKGROUND: It is uncertain if lipids or lipoproteins are associated with osteoporotic fractures. In this study, incident hip fracture risk according to conventional lipid levels and lipoprotein levels and sizes was examined.

METHODS: We followed 5832 participants aged ≥65 years from the Cardiovascular Health Study for hip fracture for a mean of 13.5 (SD 5.7) years. Standard enzymatic methods were used to determine lipid levels (HDL-c, LDL-c, triglycerides). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein fractions (VLDL-P, LDL-P, HDL-P) in a subset of 1849 participants.

RESULTS: We documented 755 incident hip fractures among women (1.19 fractures per 100 participant years [95% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95% CI, 0.41, 1.10]) over an average follow-up. HDL-c and LDL-c levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-c, p=0.009; LDL-c, p=0.02). Triglyceride levels were not significantly associated with hip fracture risk. In fully adjusted conjoint models, higher VLDL-P concentration [HR per 1-standard (SD) increment 1.47 (1.13, 1.91)] and size [HR per 1-SD increment 1.24 [1.05, 1.46]) and higher HDL-P size (HR per 1-SD increment 1.81 [1.25, 2.62]) were all associated with higher hip fracture risk.

CONCLUSIONS: Lipids and lipoproteins are associated with hip fracture risk in older adults. The associations are complex. Mechanistic studies are needed to understand these findings.

1 aBarzilay, Joshua, I1 aBůzková, Petra1 aKuller, Lewis, H1 aCauley, Jane, A1 aFink, Howard, A1 aSheets, Kerry1 aRobbins, John, A1 aCarbone, Laura, D1 aElam, Rachel, E1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/908702793nas a2200253 4500008004100000022001400041245017100055210006900226260001600295520193800311100002102249700002102270700002702291700002302318700001902341700002002360700002202380700001802402700002002420700002102440700001802461700002402479856003602503 2022 eng d a1758-535X00aThe Associations of Individual and Subclasses of Non-Esterified Fatty Acids with Disability, and Mobility Limitation in Older Adults: the Cardiovascular Health Study.0 aAssociations of Individual and Subclasses of NonEsterified Fatty c2022 Sep 263 a

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.

1 aAhiawodzi, Peter1 aBůzková, Petra1 aLichtenstein, Alice, H1 aMatthan, Nirupa, R1 aIx, Joachim, H1 aKizer, Jorge, R1 aTracy, Russell, P1 aArnold, Alice1 aNewman, Anne, B1 aSiscovick, David1 aDjoussé, Luc1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/915302059nas a2200181 4500008004100000022001400041245005900055210005700114260001600171520152400187100002101711700002001732700002001752700002101772700002401793700002401817856003601841 2023 eng d a1530-891X00aAge-Related Factors Associated with Hip Fracture Risk.0 aAgeRelated Factors Associated with Hip Fracture Risk c2023 Mar 063 a

OBJECTIVES: Advancing age is a powerful risk factor for hip fracture. The biological mechanisms through which aging impacts hip fracture risk have not been well studied.

METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with hip fracture risk are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults ages >65 years with 25 years of follow up.

RESULTS: Five age-related factors were found to be significantly associated with hip fracture risk: (1) microvascular disease of the kidney (albuminuria and / or elevated urine albumin to creatinine ratio) and of the brain (abnormal white matter disease on brain MRI); (2) increased serum levels of carboxymethyl-lysine (CML), an advanced glycation end-product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased trans-fatty acid levels in the blood. Each of these factors was associated with a 10-25%. increased risk of fracture. These associations were independent of traditional risk factors for hip fracture.

CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with hip fracture risk. These same factors may also explain the high risk for mortality following hip fracture.

1 aBůzková, Petra1 aCauley, Jane, A1 aFink, Howard, A1 aRobbins, John, A1 aMukamal, Kenneth, J1 aBarzilay, Joshua, I uhttps://chs-nhlbi.org/node/931803335nas a2200337 4500008004100000022001400041245015100055210006900206260001300275300001000288490000700298520234000305653000902645653002102654653001202675653001802687653001102705653002402716653001702740653001702757100002102774700002102795700001502816700002202831700002002853700002402873700002102897700002302918700002002941856003602961 2023 eng d a1433-296500aAssociation of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.0 aAssociation of covert brain infarcts and white matter hyperinten c2023 Jan a91-990 v343 a

UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture.

INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture.

METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive).

RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90).

CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

10aAged10aBrain Infarction10aFrailty10aHip Fractures10aHumans10aProspective Studies10aRisk Factors10aWhite Matter1 aSheets, Kerry, M1 aBůzková, Petra1 aChen, Zhao1 aCarbone, Laura, D1 aCauley, Jane, A1 aBarzilay, Joshua, I1 aStarks, Jamie, L1 aMiller, Lindsay, M1 aFink, Howard, A uhttps://chs-nhlbi.org/node/924202665nas a2200313 4500008004100000022001400041245010000055210006900155260001600224520170900240100002001949700002101969700002501990700002002015700002402035700002202059700001502081700002102096700002402117700003002141700002002171700002202191700001902213700002002232700002302252700002002275700002002295856003602315 2023 eng d a1432-082700aAssociation of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.0 aAssociation of Immune Cell Subsets with Incident Hip Fracture Th c2023 Aug 313 a

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

1 aElam, Rachel, E1 aBůzková, Petra1 aDelaney, Joseph, A C1 aFink, Howard, A1 aBarzilay, Joshua, I1 aCarbone, Laura, D1 aSaha, Rick1 aRobbins, John, A1 aMukamal, Kenneth, J1 aValderrábano, Rodrigo, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aOlson, Nels, C1 aHuber, Sally, A1 aDoyle, Margaret, F1 aLanday, Alan, L1 aCauley, Jane, A uhttps://chs-nhlbi.org/node/947802513nas a2200217 4500008004100000022001400041245016600055210006900221260001300290300001100303490000600314520179500320100001902115700002102134700002002155700002102175700002402196700002002220700001902240856003602259 2023 eng d a2473-403900aThe Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study.0 aAssociation of Tryptophan and Its Metabolites With Incident Hip  c2023 Oct ae108010 v73 a

Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( ≥ 0.64), mortality ( ≥ 0.20), or cross-sectional frailty status ( ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBarzilay, Joshua, I1 aElam, Rachel, E1 aIsales, Carlos uhttps://chs-nhlbi.org/node/949902924nas a2200337 4500008004100000022001400041245008300055210006900138260001600207300000700223490000700230520199400237653000902231653001202240653001802252653001102270653002702281653002202308100002402330700002102354700002002375700002002395700001902415700001702434700002102451700001902472700001802491700001702509700002402526856003602550 2023 eng d a1862-351400aThe associations of markers of endothelial dysfunction with hip fracture risk.0 aassociations of markers of endothelial dysfunction with hip frac c2023 Mar 02 a390 v183 a

UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them.

PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk.

METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group.

RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable.

CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

10aAged10aForearm10aHip Fractures10aHumans10aOsteoporotic Fractures10aVascular Diseases1 aBarzilay, Joshua, I1 aBůzková, Petra1 aFink, Howard, A1 aCauley, Jane, A1 aCarbone, Laura1 aElam, Rachel1 aRobbins, John, A1 aStein, Phyllis1 aSheets, Kerry1 aJalal, Diana1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/931602942nas a2200361 4500008004100000022001400041245014300055210006900198260001600267300000700283490000700290520191700297653000902214653002202223653002802245653001102273653001802284653001202302653001802314653001102332653000902343653001802352653001702370653001302387100001902400700002102419700002102440700002002461700002402481700002002505700001902525856003602544 2024 eng d a1862-351400aAssociation of serum levels of phenylalanine and tyrosine with hip fractures and frailty in older adults: The cardiovascular health study.0 aAssociation of serum levels of phenylalanine and tyrosine with h c2024 Jun 20 a510 v193 a

UNLABELLED: This study examined if the amino acids phenylalanine or tyrosine contribute to risk of hip fracture or frailty in older adults. We determined that neither phenylalanine nor tyrosine are important predictors of hip fracture or frailty. We suggest advice on protein intake for skeletal health consider specific amino acid composition.

PURPOSE: Protein is essential for skeletal health, but the specific amino acid compositions of protein may have differential associations with fracture risk. The aim of this study was to determine the association of serum levels of the aromatic amino acids phenylalanine and tyrosine with risk for incident hip fractures over twelve years of follow-up and cross sectional associations with frailty.

METHODS: We included 131 older men and women from the Cardiovascular Health Study (CHS) who sustained a hip fracture over twelve years of follow-up and 131 men and women without an incident hip fracture over this same period of time. 42% of this cohort were men and 95% were Caucasian. Weighted multivariable Cox hazards molecules were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher serum level of phenylalanine or tyrosine. Relative risk regression was used to determine the cross-sectional association of these amino acids with Freid's frailty index.

RESULTS: Neither serum levels of phenylalanine (HR 0.85 (95% CI 0.62-1.16) or tyrosine (HR 0.82 (95% CI 0.62-1.1) were significantly associated with incident hip fractures or cross sectionally with frailty (frail compared with prefrail/not frail) (HR 0.92 (95% CI 0.48-1.76) and HR (0.86 (95% CI 0.46-1.61) respectively.

CONCLUSION: Phenylalanine and tyrosine are not significant contributors to hip fractures or frailty in older men and women.

10aAged10aAged, 80 and over10aCross-Sectional Studies10aFemale10aFrail Elderly10aFrailty10aHip Fractures10aHumans10aMale10aPhenylalanine10aRisk Factors10aTyrosine1 aCarbone, Laura1 aBůzková, Petra1 aRobbins, John, A1 aFink, Howard, A1 aBarzilay, Joshua, I1 aElam, Rachel, E1 aIsales, Carlos uhttps://chs-nhlbi.org/node/970102808nas a2200205 4500008004100000022001400041245011800055210007100173260001600244520214500260100001802405700002102423700002102444700001802465700001702483700002702500700001902527700002002546856003602566 2024 eng d a1945-719700aAssociation of thyroid dysfunction in individuals ≥ 65 years of age with subclinical cardiac abnormalities.0 aAssociation of thyroid dysfunction in individuals ≥ 65 years of  c2024 Jan 063 a

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.

1 aBarasch, Eddy1 aGottdiener, John1 aBůzková, Petra1 aCappola, Anne1 aShah, Sanjiv1 aDeFilippi, Christopher1 aGardin, Julius1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/9574