@article {660, title = {Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study.}, journal = {Stroke}, volume = {32}, year = {2001}, month = {2001 Sep}, pages = {1939-46}, abstract = {

BACKGROUND AND PURPOSE: Subclinical findings on MRI of the brain are associated with poorer cognitive and neurological function among older adults. We sought to determine how alcohol consumption is related to these findings.

METHODS: As part of the Cardiovascular Health Study, 3660 adults aged 65 years and older underwent MRI of the brain from 1992 to 1994. We excluded 284 participants with a confirmed history of cerebrovascular disease. We assessed self-reported intake of beer, wine, and liquor at the annual clinic visit closest to the date of the MRI and grouped participants into 6 categories: abstainers, former drinkers, <1 drink weekly, 1 to <7 drinks weekly, 7 to <15 drinks weekly, and >/=15 drinks weekly. Neuroradiologists assessed white matter grade, infarcts, ventricular size, and sulcal size in a standardized and blinded manner. We used multivariate regression to control for sociodemographic and clinical characteristics.

RESULTS: We found a U-shaped relationship between alcohol consumption and white matter abnormalities. Compared with abstainers, individuals consuming 1 to <7 drinks had an OR of 0.68, and those consuming >/=15 drinks weekly had an OR of 0.95 (p for quadratic term=0.01). Heavier alcohol consumption was associated with a lower prevalence of infarcts (OR for >/=15 drinks weekly relative to abstainers 0.59; P for trend=0.004), but larger ventricular size (OR for >/=15 drinks weekly relative to abstainers 1.32; P for trend=0.006) and sulcal size (OR for >/=15 drinks weekly relative to abstainers 1.53; P for trend=0.007).

CONCLUSIONS: Moderate alcohol consumption is associated with a lower prevalence of white matter abnormalities and infarcts, thought to be of vascular origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older adults. The extent to which these competing associations influence overall brain function will require further study.

}, keywords = {Aged, Aging, Alcohol Drinking, Atrophy, Brain, Brain Diseases, Cerebral Infarction, Comorbidity, Demography, Female, Health Surveys, Humans, Logistic Models, Longitudinal Studies, Magnetic Resonance Imaging, Male, Nerve Fibers, Myelinated, Odds Ratio, Prospective Studies, Sensitivity and Specificity, United States}, issn = {1524-4628}, doi = {10.1161/hs0901.095723}, author = {Mukamal, K J and Longstreth, W T and Mittleman, M A and Crum, R M and Siscovick, D S} } @article {944, title = {Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study.}, journal = {Osteoporos Int}, volume = {18}, year = {2007}, month = {2007 May}, pages = {593-602}, abstract = {

INTRODUCTION: Previous studies have found inconsistent relationships of alcohol consumption with risk of hip fracture, and the importance of bone mineral density and risk of falls in mediating such a relationship has not been determined.

METHODS: As part of the Cardiovascular Health Study, a population-based cohort study of adults aged 65 years and older from four U.S. communities, 5,865 participants reported their use of beer, wine, and liquor yearly. We identified cases of hip fracture unrelated to malignancy or motor vehicle accidents using hospitalization discharge diagnoses. A subgroup of 1,567 participants in two communities underwent dual-energy x-ray absorptiometry scans to assess bone mineral density.

RESULTS: A total of 412 cases of hip fracture occurred during an average of 12 years of follow-up. There was a significant U-shaped relationship between alcohol intake and risk of hip fracture (p quadratic 0.02). Compared with long-term abstainers, the adjusted hazard ratios for hip fracture were 0.78 (95\% confidence interval [CI], 0.61-1.00) among consumers of up to 14 drinks per week and 1.18 (95\% CI, 0.77-1.81) among consumers of 14 or more drinks per week. Alcohol intake was associated with bone mineral density of the total hip and femoral neck in a stepwise manner, with approximately 5\% (95\% CI, 1\%-9\%) higher bone density among consumers of 14 or more drinks per week than among abstainers. These relationships were all similar among men and women.

CONCLUSIONS: Among older adults, moderate alcohol consumption has a U-shaped relationship with risk of hip fracture, but a graded positive relationship with bone mineral density at the hip.

}, keywords = {Absorptiometry, Photon, Aged, Alcohol Drinking, Alcoholic Beverages, Apolipoproteins E, Bone Density, Female, Femur Neck, Genotype, Hip, Hip Fractures, Humans, Longitudinal Studies, Male, Risk Assessment, Risk Factors, Sex Distribution, United States}, issn = {0937-941X}, doi = {10.1007/s00198-006-0287-7}, author = {Mukamal, K J and Robbins, J A and Cauley, J A and Kern, L M and Siscovick, D S} } @article {1250, title = {Lipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study.}, journal = {Diabetologia}, volume = {54}, year = {2011}, month = {2011 Feb}, pages = {329-33}, abstract = {

AIMS/HYPOTHESIS: Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.

METHODS: We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.

RESULTS: At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95\% CI 1.31-2.15] vs OR 1.67 [95\% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.

CONCLUSIONS/INTERPRETATION: In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Cardiovascular Diseases, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Male, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1432-0428}, doi = {10.1007/s00125-010-1969-4}, author = {Nelson, T L and Kamineni, A and Psaty, B and Cushman, M and Jenny, N S and Hokanson, J and Furberg, C and Mukamal, K J} } @article {1369, title = {Lipoprotein-associated phospholipase A2 (Lp-PLA2) and future risk of type 2 diabetes: results from the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 May}, pages = {1695-701}, abstract = {

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.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Aged, 80 and over, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Incidence, Insulin Resistance, Male, Middle Aged, Predictive Value of Tests, Prevalence, Prospective Studies, Risk, Risk Factors}, issn = {1945-7197}, doi = {10.1210/jc.2011-3026}, author = {Nelson, T L and Biggs, M L and Kizer, J R and Cushman, M and Hokanson, J E and Furberg, C D and Mukamal, K J} } @article {6281, title = {Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies.}, journal = {Int J Obes (Lond)}, volume = {37}, year = {2013}, month = {2013 Sep}, pages = {1211-20}, abstract = {

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids.

DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800).

RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed.

CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

}, keywords = {Adipose Tissue, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Body Mass Index, Europe, European Continental Ancestry Group, Fatty Acids, Female, Gene Frequency, Gene-Environment Interaction, Genetic Predisposition to Disease, Genotype, Humans, Low Density Lipoprotein Receptor-Related Protein-1, Male, Middle Aged, Obesity, Phenotype, Polymorphism, Single Nucleotide, Prevalence, United States}, issn = {1476-5497}, doi = {10.1038/ijo.2012.215}, author = {Smith, C E and Ngwa, J and Tanaka, T and Qi, Q and Wojczynski, M K and Lemaitre, R N and Anderson, J S and Manichaikul, A and Mikkil{\"a}, V and van Rooij, F J A and Ye, Z and Bandinelli, S and Frazier-Wood, A C and Houston, D K and Hu, F and Langenberg, C and McKeown, N M and Mozaffarian, D and North, K E and Viikari, J and Zillikens, M C and Djouss{\'e}, L and Hofman, A and K{\"a}h{\"o}nen, M and Kabagambe, E K and Loos, R J F and Saylor, G B and Forouhi, N G and Liu, Y and Mukamal, K J and Chen, Y-D I and Tsai, M Y and Uitterlinden, A G and Raitakari, O and van Duijn, C M and Arnett, D K and Borecki, I B and Cupples, L A and Ferrucci, L and Kritchevsky, S B and Lehtim{\"a}ki, T and Qi, Lu and Rotter, J I and Siscovick, D S and Wareham, N J and Witteman, J C M and Ordov{\'a}s, J M and Nettleton, J A} } @article {5859, title = {Prediction and classification of cardiovascular disease risk in older adults with diabetes.}, journal = {Diabetologia}, volume = {56}, year = {2013}, month = {2013 Feb}, pages = {275-83}, abstract = {

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.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Biomarkers, Blood Pressure, Cardiovascular Diseases, Carotid Intima-Media Thickness, Cholesterol, HDL, Diabetes Mellitus, Female, Humans, Male, Myocardial Infarction, Regression Analysis, Risk Factors, Stroke}, issn = {1432-0428}, doi = {10.1007/s00125-012-2772-1}, author = {Mukamal, K J and Kizer, J R and Djouss{\'e}, L and Ix, J H and Zieman, S and Siscovick, D S and Sibley, C T and Tracy, R P and Arnold, A M} } @article {7134, title = {The association of lean and fat mass with all-cause mortality in older adults: The Cardiovascular Health Study.}, journal = {Nutr Metab Cardiovasc Dis}, year = {2016}, month = {2016 Jun 28}, abstract = {

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~{\textpm}~4.8 years (56\% women) with mean body mass index 27.1~{\textpm}~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.

}, issn = {1590-3729}, doi = {10.1016/j.numecd.2016.06.011}, author = {Spahillari, A and Mukamal, K J and DeFilippi, C and Kizer, J R and Gottdiener, J S and Djouss{\'e}, L and Lyles, M F and Bartz, T M and Murthy, V L and Shah, R V} } @article {7124, title = {Brain natriuretic peptide and insulin resistance in older adults.}, journal = {Diabet Med}, year = {2016}, month = {2016 Apr 21}, abstract = {

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.

}, issn = {1464-5491}, doi = {10.1111/dme.13139}, author = {Kim, F and Biggs, M L and Kizer, J R and Brutsaert, E F and de Fillipi, C and Newman, A B and Kronmal, R A and Tracy, R P and Gottdiener, J S and Djouss{\'e}, L and de Boer, I H and Psaty, B M and Siscovick, D S and Mukamal, K J} } @article {6806, title = {Fibrosis markers, hip fracture risk, and bone density in older adults.}, journal = {Osteoporos Int}, volume = {27}, year = {2016}, month = {2016 Feb}, pages = {815-20}, abstract = {

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.

}, issn = {1433-2965}, doi = {10.1007/s00198-015-3269-9}, author = {Barzilay, J I and B{\r u}{\v z}kov{\'a}, P and Kizer, J R and Djouss{\'e}, L and Ix, J H and Fink, H A and Siscovick, D S and Cauley, J A and Mukamal, K J} } @article {7119, title = {Systemic markers of microvascular disease and bone mineral density in older adults : The cardiovascular health study.}, journal = {Osteoporos Int}, volume = {27}, year = {2016}, month = {2016 Nov}, pages = {3217-3225}, abstract = {

Here we report that abnormal brain white matter and, to a lesser extent, albuminuria are associated with reduced bone mineral density in the hip, spine, and total body in men and women. These findings may explain the increased hip fracture risk reported in some studies in association with microvascular disorders.

INTRODUCTION: Markers of microvascular disease have been individually associated with increased risk of osteoporotic fractures in some studies. Here, we examine whether these markers are associated with reduced bone mineral density (BMD) individually and together.

METHODS: BMD testing using dual x-ray absorptiometry of the hip, lumbar spine, and total body was performed in 1473 participants from the Cardiovascular Health Study (mean age~~~78~years): 1215 were assessed for urinary albumin-creatinine ratio, 944 for abnormal white matter disease (AWMD) by brain MRI, and 541 for retinal vascular disease with fundus photographs. Linear regression models were used to evaluate the cross-sectional association of each marker with BMD accounting for potentially confounding factors.

RESULTS: AWMD was associated with lower hip, spine, and total body BMD in women (β -3.08 to -4.53; p~<~0.01 for all) and lower hip and total body BMD in men (β -2.90 to -4.24; p~=~0.01-0.03). Albuminuria was associated with lower hip (β -3.37; p~=~.05) and total body (β -3.21; p~=~.02) BMD in men, but not in women. The associations of AWMD and albuminuria with BMD persisted with mutual adjustment and appeared to be additive to each other. Retinal vascular disease was not associated with BMD in men or women.

CONCLUSION: AWMD and, to a lesser extent, albuminuria were independently associated with lower BMD, suggesting that microvascular disease may play a role in the pathogenesis of reduced BMD. These findings need to be confirmed by longitudinal studies.

}, issn = {1433-2965}, doi = {10.1007/s00198-016-3649-9}, author = {Barzilay, J I and B{\r u}{\v z}kov{\'a}, P and Fink, H A and Cauley, J A and Robbins, J A and Garimella, P S and Jalal, D I and Mukamal, K J} } @article {7803, title = {The associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults.}, journal = {Osteoporos Int}, volume = {29}, year = {2018}, month = {08/2018}, pages = {2230}, chapter = {2219}, abstract = {In 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 {\textpm} 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.}, keywords = {Bone mineral density, Hip fracture, Risk, Subclinical atherosclerosis}, doi = {10.1007/s00198-018-4611-9}, url = {https://www.ncbi.nlm.nih.gov/pubmed/30132027}, author = {Barzilay, JI and B{\r u}zkov{\'a}, Petra and Cauley, J A and Robbins, J. A. and Fink, Howard A and Mukamal, K J} } @article {7666, title = {Fasting and post-glucose load measures of insulin resistance and risk of incident atrial fibrillation: The Cardiovascular Health Study.}, journal = {Nutr Metab Cardiovasc Dis}, year = {2018}, month = {2018 Mar 02}, abstract = {

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.

}, issn = {1590-3729}, doi = {10.1016/j.numecd.2018.02.016}, author = {Garg, P K and Biggs, M L and Kaplan, R and Kizer, J R and Heckbert, S R and Mukamal, K J} } @article {8098, title = {Assessing risk factors of non-fatal outcomes amid a competing risk of mortality: the example of hip fracture.}, journal = {Osteoporos Int}, year = {2019}, month = {2019 Jun 29}, abstract = {

The Fine-Gray method is often used instead of Cox regression to account for competing risks of death in time-to-event analyses for non-fatal outcomes. A series of examples using well-known risk factors of hip fracture in an older cohort with substantial competing mortality demonstrates that the Fine-Gray approach can yield estimates that implausibly contradict long-established associations, while Cox regression preserves them. Cox regression is generally preferred for risk factor-outcome associations even in the presence of competing risk of death.

INTRODUCTION: Factors like age, sex, and race are associated not only with risk of hip fracture but also with mortality. Substantial misunderstanding remains regarding the appropriate statistical approach to account for the competing risk of mortality.

METHODS: In the Cardiovascular Health Study, an ongoing cohort study of 5888 older adults, we followed participants for incident hip fracture from their 1992-1993 visit through June 2014. We contrasted the conventional cause-specific Cox analysis, which censors individuals at the time of death, with the Fine-Gray (FG) approach, which extends participant follow-up even after death, to estimate the association of well-established demographic and clinical factors with incident hip fracture.

RESULTS: For age, current smoking and sex, Cox and FG methods yielded directionally concordant but quantitatively different strengths of association. For example, the Cox hazard ratio (HR) for a 5-year increment in age was 1.74 (95\% CI, 1.61-1.87), while the corresponding FG HR was 1.16 (1.09-1.24). In contrast, the FG approach estimated a stronger association of hip fracture with sex. The two approaches yielded nearly identical results for race. For diabetes and kidney function, the estimates were discordant in direction, and the FG HRs suggested effects that were in the opposite direction of well-understood and widely accepted associations.

CONCLUSIONS: Cause-specific Cox models provide appropriate estimates of hazard for non-fatal outcomes like hip fracture even in the presence of competing risk of mortality. The Cox approach estimates hazard in the population of individuals who have not yet had an incident hip fracture and remain alive, which is typically the group of clinical interest. The Fine-Gray method estimates hazard in a hypothetical population that can yield misleading inferences about risk factors in populations of clinical interest.

}, issn = {1433-2965}, doi = {10.1007/s00198-019-05048-w}, author = {B{\r u}{\v z}kov{\'a}, P and Barzilay, J I and Mukamal, K J} } @article {8106, title = {Biochemical markers of bone turnover and risk of incident hip fracture in older women: the Cardiovascular Health Study.}, journal = {Osteoporos Int}, year = {2019}, month = {2019 Jun 21}, abstract = {

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.

}, issn = {1433-2965}, doi = {10.1007/s00198-019-05043-1}, author = {Massera, D and Xu, S and Walker, M D and Valderr{\'a}bano, R J and Mukamal, K J and Ix, J H and Siscovick, D S and Tracy, R P and Robbins, J A and Biggs, M L and Xue, X and Kizer, J R} } @article {8702, title = {Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study.}, journal = {Osteoporos Int}, year = {2021}, month = {2021 Mar 02}, abstract = {

Among elderly participants from the Cardiovascular Health Study, we found that non-esterified trans fatty acid levels had a significant prospective association with hip fracture risk. Other non-esterified fatty acid classes were not associated with hip fracture risk.

INTRODUCTION: Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined.

METHODS: Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models.

RESULTS: We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95\% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively).

CONCLUSION: Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

}, issn = {1433-2965}, doi = {10.1007/s00198-021-05897-4}, author = {Barzilay, J I and B{\r u}{\v z}kov{\'a}, P and Djouss{\'e}, L and Ix, J and Kizer, J and Cauley, J and Matthan, N and Lichtenstein, A H and Mukamal, K J} }