Extent of Abdominal Aortic Calcification Is Associated With Incident Rapid Weight Loss Over 5 Years: The Perth Longitudinal Study of Ageing Women.

BACKGROUND: Abdominal aortic calcification (AAC), a marker of vascular disease, is associated with disease in other vascular beds including gastrointestinal arteries. We investigated whether AAC is related to rapid weight loss over 5 years and whether rapid weight loss is associated with 9.5-year all-cause mortality in community-dwelling older women. METHODS: Lateral spine images from dual-energy x-ray absorptiometry (1998/1999) were used to assess AAC (24-point AAC scoring method) in 929 older women. Over 5 years, body weight was assessed at 12-month intervals. Rapid weight loss was defined as >5% decrease in body weight within any 12-month interval. Multivariable-adjusted logistic regression was used to assess AAC and rapid weight loss and Cox regression to assess the relationship between rapid weight loss and 9.5-year all-cause mortality. RESULTS: Mean±SD age of women was 75.0±2.6 years. During the initial 5 years, 366 (39%) women presented with rapid weight loss. Compared with women with low AAC (24-point AAC score 0-1), those with moderate (24-point AAC score 2-5: odds ratio, 1.36 [95% CI, 1.00-1.85]) and extensive (24-point AAC score 6+: odds ratio, 1.59 [95% CI, 1.10-2.31]) AAC had higher odds for presenting with rapid weight loss. Results remained similar after further adjustment for dietary factors (alcohol, protein, fat, and carbohydrates), diet quality, blood pressure, and cholesterol measures. The estimates were similar in subgroups of women who met protein intake (n=599) and physical activity (n=735) recommendations (extensive AAC: odds ratios, 1.81 [95% CI, 1.12-2.92] and 1.58 [95% CI, 1.02-2.44], respectively). Rapid weight loss was associated with all-cause mortality over the next 9.5 years (hazard ratio, 1.49 [95% CI, 1.17-1.89]; P=0.001). CONCLUSIONS: AAC extent was associated with greater risk for rapid weight loss over 5 years in older women, a risk for all-cause mortality. Since the association was unchanged after taking nutritional intakes into account, these data support the possibility that vascular disease may play a role in the maintenance of body weight.

Higher plant-derived nitrate intake is associated with lower odds of frailty in a cross-sectional study of community-dwelling older women.

PURPOSE: Dietary nitrate intake is inversely related to numerous contributors towards frailty, including cardiovascular disease and poor physical function. Whether these findings extend to frailty remain unknown. We investigated if habitual nitrate intake, derived from plants or animal-based foods, was cross-sectionally associated with frailty in women. METHODS: Community-dwelling older Australian women (n = 1390, mean age 75.1 ± 2.7 years) completed a validated semi-quantitative food frequency questionnaire (FFQ). Nitrate concentrations in food were obtained from international nitrate databases. We adopted the Rockwood frailty index (FI) of cumulative deficits comprising 33 variables across multiple health domains (scored 0 to 1), which predicts increased hospitalisation and mortality risk. A FI ≥ 0.25 indicated frailty. Cross-sectional associations between nitrate intake (total plant and animal nitrate, separately) and frailty were analysed using multivariable-adjusted logistic regression models (including lifestyle factors), as part of restricted cubic splines. RESULTS: A non-linear inverse relationship was observed between total plant nitrate intake and frailty. Compared to women with the lowest plant nitrate intake (Quartile [Q]1), women with greater intakes in Q2 (OR 0.69 95%CI 0.56-0.84), Q3 (OR 0.67 95%CI 0.50-0.90) and Q4 (OR 0.66 95%CI 0.45-0.98) had lower odds for frailty. A nadir in the inverse association was observed once intakes reached ~ 64 mg/d (median Q2). No relationship was observed between total animal nitrate and frailty. CONCLUSION: Community-dwelling older women consuming low amounts of plant-derived nitrate were more likely to present with frailty. Consuming at least one daily serving (~ 75 g) of nitrate-rich green leafy vegetables may be beneficial in preventing frailty.

Vitamin K1 intake is associated with lower risk for all-cause and cardiovascular disease mortality in community-dwelling older Australian women.

BACKGROUND AND AIMS: Assessing the relationship between vitamin K1 intakes, using region-specific food databases, with both all-cause, and cardiovascular disease (CVD) mortality warrants further investigation to inform future preventative strategies. Consequently, we examined the aforementioned associations in the Perth Longitudinal Study of Ageing Women (PLSAW). METHODS AND RESULTS: 1436 community-dwelling older Australian women (mean ± SD age 75.2 ± 2.7 years) completed a validated food frequency questionnaire at baseline (1998). Vitamin K1 intake was calculated based on an Australian vitamin K food database, supplemented with published data. All-cause and CVD mortality data was obtained from linked health records. Associations were examined using restricted cubic splines within Cox-proportional hazard models, adjusted for a range of cardiovascular and lifestyle related risk factors. Over 15 years of follow-up, 601 (41.9%) women died, with 236 deaths (16.4%) due to CVD. Compared to women with the lowest vitamin K1 intakes (Quartile 1, median 49.1 µg/day), those with the highest intakes (Quartile 4, median 119.3 µg/day) had lower relative hazards for all-cause mortality (HR 0.66 95%CI 0.51-0.86) and CVD mortality (HR 0.61 95%CI 0.41-0.92). A plateau in the inverse association was observed from vitamin K1 intakes of approximately ≥80 µg/day. CONCLUSION: Higher vitamin K1 intakes were associated with lower risk for both all-cause and CVD mortality in community-dwelling older women, independent of CVD related risk factors. A higher intake of vitamin K1 rich foods, such as leafy green vegetables, may support cardiovascular health.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Higher Habitual Dietary Flavonoid Intake Associates With Less Extensive Abdominal Aortic Calcification in a Cohort of Older Women.

BACKGROUND: The extent of abdominal aortic calcification (AAC) is a major predictor of vascular disease events. We have previously found regular apple intake, a major source of dietary flavonoids, associates with lower AAC. Whether total dietary flavonoid intake impacts AAC remains unknown. Here, we extend our observations to habitual intakes of total flavonoids, flavonoid subclasses, and specific flavonoid-containing foods, with the odds of extensive AAC. METHODS: We conducted cross-sectional analyses on 881 females (median [interquartile range] age, 80 [78-82] years; body mass index, 27 [24-30] kg/m2) from the PLSAW (Perth Longitudinal Study of Ageing Women). Flavonoid intake was calculated from food-frequency questionnaires. Calcifications of the abdominal aorta were assessed on lateral lumbar spine images and categorized as less extensive or extensive. Logistic regression was used to investigate associations. RESULTS: After adjusting for demographic, lifestyle and dietary confounders, participants with higher (Q4), compared with lower (Q1) intakes, of total flavonoids, flavan-3-ols, and flavonols had 36% (odds ratio [95% CI], 0.64 [0.43-0.95]), 39% (0.61 [0.40-0.93]) and 38% (0.62 [0.42-0.92]) lower odds of extensive AAC, respectively. In food-based analyses, higher black tea intake, the main source of total flavonoids (75.9%), associated with significantly lower odds of extensive AAC (2-6 cups/d had 16%-42% lower odds compared with 0 daily intake). In a subset of nonconsumers of black tea, the association of total flavonoid intake with AAC remained (Q4 versus Q1 odds ratio [95% CI], 0.11 [0.02-0.54]). CONCLUSIONS: In older women, greater habitual dietary flavonoid intake associates with less extensive AAC.

Measures of carotid atherosclerosis and fall-related hospitalization risk: The Perth Longitudinal Study of Ageing Women.

BACKGROUND AND AIMS: We and others have identified links between cardiovascular conditions and poor musculoskeletal health. However, the relationship between measures of carotid atherosclerosis such as focal carotid plaque and common carotid intima media thickness (CCA-IMT) and falls remains understudied. This study examined the association between measures of carotid atherosclerosis and fall-related hospitalization over 11.5 years in community dwelling older women. METHODS AND RESULTS: 1116 older women recruited in 1998 to a five-year randomized controlled trial to examine the effect of calcium supplementation in preventing fracture and who had undertaken B-mode ultrasound in 2001 (three years after the baseline clinical visit) were included in this study. The participants were followed for over 11.5 years as Perth Longitudinal Study of Ageing Women (PLSAW). Over the follow up period, 428 (38.4%) women experienced a fall-related hospitalization. Older women with carotid plaque had 44% a higher relative hazard for fall-related hospitalization (HR 1.44; 95%CI, 1.18 to 1.76) compared to those without carotid plaque. The association persisted after adjustment for established falls risk factors such as measures of muscle strength and physical function.Each SD increase in the mean and maximum CCA-IMT was also associated with a higher risk of fall-related hospitalizations (HR 1.10; 95%CI, 1.00 to 1.21 and HR 1.11; 95%CI, 1.01 to 1.22, respectively). CONCLUSIONS: Measures of carotid atherosclerosis are associated with a higher risk of fall-related hospitalization independent of established falls risk factors. These findings suggest the importance of vascular health when considering falls risk.

Association of Abdominal Aortic Calcification with Peripheral Quantitative Computed Tomography Bone Measures in Older Women: The Perth Longitudinal Study of Ageing Women.

We have previously shown that abdominal aortic calcification (AAC), a marker of advanced atherosclerotic disease, is weakly associated with reduced hip areal bone mineral density (aBMD). To better understand the vascular-bone health relationship, we explored this association with other key determinants of whole-bone strength and fracture risk at peripheral skeletal sites. This study examined associations of AAC with peripheral quantitative computed tomography (pQCT)-assessed total, cortical and trabecular volumetric BMD (vBMD), bone structure and strength of the radius and tibia among 648 community-dwelling older women (mean ± SD age 79.7 ± 2.5 years). We assessed associations between cross-sectional (2003) and longitudinal (progression from 1998/1999-2003) AAC assessed on lateral dual-energy X-ray absorptiometry (DXA) images with cross-sectional (2003) and longitudinal (change from 2003 to 2005) pQCT bone measures at the 4% radius and tibia, and 15% radius. Partial Spearman correlations (adjusted for age, BMI, calcium treatment) revealed no cross-sectional associations between AAC and any pQCT bone measures. AAC progression was not associated with any bone measure after adjusting for multiple comparisons, despite trends for inverse correlations with total bone area at the 4% radius (rs = - 0.088, p = 0.044), 4% tibia (rs = - 0.085, p = 0.052) and 15% radius (rs = - 0.101, p = 0.059). Neither AAC in 2003 nor AAC progression were associated with subsequent 2-year pQCT bone changes. ANCOVA showed no differences in bone measures between women with and without AAC or AAC progression, nor across categories of AAC extent. Collectively, these finding suggest that peripheral bone density and structure, or its changes with age, are not associated with central vascular calcification in older women.

Dietary plant and animal protein intake and decline in estimated glomerular filtration rate among elderly women: a 10-year longitudinal cohort study.

BACKGROUND: Many older women demonstrate an age-related accelerating rate of renal decline that is associated with increased rates of bone disease, cardiovascular disease and mortality. Population-based protein restriction has been studied principally in patients with reduced renal function. In this investigation, we examined the hypothesis of a differential effect of plant-derived protein compared with animal-derived protein on renal function in older women. METHODS: We assessed dietary intake from a validated food frequency questionnaire and the estimated glomerular filtration rate (eGFR) (using the Chronic Kidney Disease Epidemiology Collaboration creatinine and cystatin C equation) at baseline, 5 and 10 years in the Longitudinal Study of Aging Women cohort. We tested the association between plant- and animal-sourced protein intake and kidney function using linear mixed modeling. RESULTS: A total of 1374 Caucasian women [mean (standard deviation, SD) age = 75 years (2.7) and mean (SD) baseline eGFR = 65.6 mL/min/1.73 m2 (13.1)] contributed to the analysis. The average decline in eGFR was 0.64 mL/min/1.73 m2/year [95% confidence interval (CI) 0.56-0.72]. Higher intakes of plant-sourced protein were associated with slower declines in eGFR after adjusting for covariates including animal protein and energy intake (P = 0.03). For each 10 g of plant protein, the yearly decline in eGFR was reduced by 0.12 mL/min/1.73 m2 (95% CI 0.01-0.23), principally associated with fruit-, vegetable- and nut-derived protein. The intake of animal protein was not associated with eGFR decline (P = 0.84). CONCLUSIONS: Older women consuming a diet that is richer in plant-sourced protein have a slower decline in kidney function. These data extend support for the health benefits of plant-rich diets in the general population to maintain kidney health.

Cruciferous vegetable intake is inversely associated with extensive abdominal aortic calcification in elderly women: a cross-sectional study.

We have previously shown that higher intake of cruciferous vegetables is inversely associated with carotid artery intima-media thickness. To further test the hypothesis that an increased consumption of cruciferous vegetables is associated with reduced indicators of structural vascular disease in other areas of the vascular tree, we aimed to investigate the cross-sectional association between cruciferous vegetable intake and extensive calcification in the abdominal aorta. Dietary intake was assessed, using a FFQ, in 684 older women from the Calcium Intake Fracture Outcome Study. Cruciferous vegetables included cabbage, Brussels sprouts, cauliflower and broccoli. Abdominal aortic calcification (AAC) was scored using the Kauppila AAC24 scale on dual-energy X-ray absorptiometry lateral spine images and was categorised as 'not extensive' (0-5) or 'extensive' (≥6). Mean age was 74·9 (sd 2·6) years, median cruciferous vegetable intake was 28·2 (interquartile range 15·0-44·7) g/d and 128/684 (18·7 %) women had extensive AAC scores. Those with higher intakes of cruciferous vegetables (>44·6 g/d) were associated with a 46 % lower odds of having extensive AAC in comparison with those with lower intakes (<15·0 g/d) after adjustment for lifestyle, dietary and CVD risk factors (ORQ4 v. Q1 0·54, 95 % CI 0·30, 0·97, P = 0·036). Total vegetable intake and each of the other vegetable types were not related to extensive AAC (P > 0·05 for all). This study strengthens the hypothesis that higher intake of cruciferous vegetables may protect against vascular calcification.

Vegetable diversity in relation with subclinical atherosclerosis and 15-year atherosclerotic vascular disease deaths in older adult women.

PURPOSE: Increasing vegetable intake and diversity are recommended to maintain better health. Evidence for the health benefits of vegetable diversity, separate from total intake, is scarce. We aimed to investigate the associations of vegetable diversity with subclinical measures of atherosclerosis and atherosclerotic vascular disease (ASVD) mortality. METHODS: Vegetable diversity was assessed within a validated food frequency questionnaire using a single question, 'How many different vegetables do you usually consume each day (< 1 to ≥ 6 per day)'. Cox proportional hazards modelling was used to examine the association between vegetable diversity and ASVD mortality in 1226 women aged ≥ 70 years without clinical ASVD or diabetes mellitus at baseline (1998). In 2001, B-mode ultrasonography was used to measure common carotid artery intima-media thickness (CCA-IMT) (n = 954) and carotid plaque severity (n = 968). RESULTS: Over 15 years (15,947 person-years) of follow-up, 238 ASVD-related deaths were recorded. For each additional different vegetable consumed per day, there was 17% lower hazard for ASVD mortality (HR = 0.83, 95% CI 0.78, 0.93, P = 0.001); a 1.7% lower mean CCA-IMT (B ± SE: - 0.013 ± 0.004, P < 0.001); and a 1.8% lower maximum CCA-IMT (B ± SE: - 0.017 ± 0.004, P < 0.001). Further adjustment for total vegetable intake attenuated the association between vegetable diversity and ASVD mortality (P = 0.114), but not CCA-IMT (P = 0.024). No association was observed between vegetable diversity and carotid plaque severity (P > 0.05). CONCLUSIONS: Vegetable diversity may contribute to benefits in lowering risk of ASVD in older women. The reduction in risk is partly explained by increased total vegetable consumption. CLINICAL TRIAL REGISTRY: The Perth Longitudinal Study of Aging in Women (PLSAW) trial registration ID is ACTRN12617000640303. This study was retrospectively registered on the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au.

Dietary inflammatory index and the aging kidney in older women: a 10-year prospective cohort study.

PURPOSE: Chronic inflammation plays a role in the pathogenesis of age-related renal disease and the diet can moderate systemic inflammation. The primary objective of this study was to examine the associations between a dietary inflammatory index (DII®) score and renal function, the trajectory of renal function decline, and renal disease-related hospitalizations and/or mortality over 10 years. METHODS: The study was conducted in 1422 Western Australian women without prevalent chronic kidney disease and aged ≥ 70 years. Baseline dietary data, obtained from a validated food frequency questionnaire, were used to calculate a DII score for each individual. RESULTS: In this cohort, the mean [range] DII score was 0.19 [- 6.14 to 6.39]. A higher DII score was associated with poorer renal function at baseline and a greater renal function decline over 10 years; after multivariable adjustments, a one-unit higher DII score was associated with a 0.55 mL/min/1.73 m2 lower eGFR at baseline (p = 0.01) and a 0.06 mL/min/1.73 m2 greater annual decline in eGFR over 10 years (p = 0.05). Restricted cubic splines provide evidence of a non-linear association between baseline DII score and risk of a renal disease-related event. Compared to participants in the lowest quintile, those in the highest quintile of DII score were at a higher risk of experiencing a renal disease-related event (adjusted HR 2.06, 95% CI 0.97, 4.37). CONCLUSION: Recommending an increased consumption of foods with a higher anti-inflammatory potential could form part of a multifaceted approach to reduce the risk of renal disease through diet and lifestyle changes.

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

Aortic Calcification is Associated with Five-Year Decline in Handgrip Strength in Older Women.

The objective of the study was to determine the association between AAC and neuromuscular function over 5 years. Participants in this study were ambulant women over 70 years old residing in Perth, Western Australia who participated in the Calcium Intake Fracture Outcomes Study, a randomised controlled trial of calcium supplementation. 1046 women (mean age = 74.9 ± 2.6 years; BMI = 27.1 ± 4.4 kg/m2) were included. Lateral spine images captured during bone density testing were scored for AAC (AAC24; 0-24) at baseline. Severe AAC (AACsev) was defined using established cut points (AAC24 ≥ 6). At baseline and follow-up, isometric grip strength was assessed using a dynamometer. Mobility was assessed by the Timed-Up-and-Go (TUG) test. Using pre-defined criteria, muscle weakness was considered as grip strength < 22 kg and poor mobility defined as TUG > 10.2 s. A subset of women had appendicular lean mass (ALM) determined by dual-energy X-ray absorptiometry at baseline and follow-up (n = 261). AACsev was evident in 193 (18.5%) women. Average decline in grip strength after 5 years was greater in those with AACsev than those without (3.6 ± 3.7 vs. 2.9 ± 4.2 kg; p = 0.034). This remained significant after adjustment for age, treatment allocation, diabetes, smoking history, renal function, medical record-derived prevalent vascular disease, BMI and physical activity (ß = - 0.184; 95% confidence interval: - 0.361, - 0.008; p = 0.040). AACsev was not associated with 5-year changes in TUG or ALM in univariable or multivariable analyses (all p > 0.05). In older women, severe aortic calcification was associated with greater 5-year decline in muscle strength, but not TUG or ALM. These findings support the concept that vascular disease may have an effect on the loss of muscular strength.

Vegetable and fruit intake and injurious falls risk in older women: a prospective cohort study.

The role of vegetable and fruit intake in reducing falls risk in elderly populations is uncertain. This study examined the associations of vegetable and fruit intake with falls-related hospitalisations in a prospective cohort study of elderly women (n 1429, ≥70 years), including effects on muscular function, which represented a potential causal pathway. Muscular function, measured using grip strength and timed-up-and-go (TUG), and vegetable and fruit intake, quantified using a validated FFQ, were assessed at baseline (1998). Incident falls-related hospitalisation over 14·5-year follow-up was captured by the Hospital Morbidity Data Collection, linked via the Western Australian Data Linkage System. Falls-related hospitalisation occurred in 568 (39·7 %) of women. In multivariable-adjusted models, falls-related hospitalisations were lower in participants consuming more vegetables (hazard ratio (HR) per 75 g serve: 0·90 (95 % CI 0·82, 0·99)), but not fruit intake (per 150 g serve: 1·03 (95 % CI 0·93, 1·14)). Only total cruciferous vegetable intake was inversely associated with falls-related hospitalisation (HR: per 20 g serve: 0·90 (95 % CI 0·83, 0·97)). Higher total vegetable intake was associated with lower odds for poor grip strength (OR: 0·87 (95 % CI 0·77, 0·97)) and slow TUG (OR: 0·88 (95 % CI 0·78, 0·99)). Including grip strength and TUG in the multivariable-adjusted model attenuated the association between total vegetable intake and falls-related hospitalisations. In conclusion, elderly women with higher total and cruciferous vegetable intake had lower injurious falls risk, which may be explained in a large part by better physical function. Falls reduction may be considered an additional benefit of higher vegetable intake in older women.

Association of Vegetable Nitrate Intake With Carotid Atherosclerosis and Ischemic Cerebrovascular Disease in Older Women.

BACKGROUND AND PURPOSE: A short-term increase in dietary nitrate (NO3-) improves markers of vascular health via formation of nitric oxide and other bioactive nitrogen oxides. Whether this translates into long-term vascular disease risk reduction has yet to be examined. We investigated the association of vegetable-derived nitrate intake with common carotid artery intima-media thickness (CCA-IMT), plaque severity, and ischemic cerebrovascular disease events in elderly women (n=1226). METHODS: Vegetable nitrate intake, lifestyle factors, and cardiovascular disease risk factors were determined at baseline (1998). CCA-IMT and plaque severity were measured using B-mode carotid ultrasound (2001). Complete ischemic cerebrovascular disease hospitalizations or deaths (events) over 14.5 years (15 032 person-years of follow-up) were obtained from the West Australian Data Linkage System. RESULTS: Higher vegetable nitrate intake was associated with a lower maximum CCA-IMT (B=-0.015, P=0.002) and lower mean CCA-IMT (B=-0.012, P=0.006). This relationship remained significant after adjustment for lifestyle and cardiovascular risk factors (P≤0.01). Vegetable nitrate intake was not a predictor of plaque severity. In total 186 (15%) women experienced an ischemic cerebrovascular disease event. For every 1 SD (29 mg/d) higher intake of vegetable nitrate, there was an associated 17% lower risk of 14.5-year ischemic cerebrovascular disease events in both unadjusted and fully adjusted models (P=0.02). CONCLUSIONS: Independent of other risk factors, higher vegetable nitrate was associated with a lower CCA-IMT and a lower risk of an ischemic cerebrovascular disease event.

Identification of a novel FGFRL1 MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies.

MicroRNAs (miRNAs) are critical post-transcriptional regulators. Based on a previous genome-wide association (GWA) scan, we conducted a polymorphism in microRNA target sites (poly-miRTS)-centric multistage meta-analysis for lumbar spine (LS)-, total hip (HIP)- and femoral neck (FN)-bone mineral density (BMD). In stage I, 41 102 poly-miRTSs were meta-analyzed in seven cohorts with a genome-wide significance (GWS) α = 0.05/41 102 = 1.22 × 10(-6). By applying α = 5 × 10(-5) (suggestive significance), 11 poly-miRTSs were selected, with FGFRL1 rs4647940 and PRR5 rs3213550 as top signals for FN-BMD (P = 7.67 × 10(-6) and 1.58 × 10(-5)) in gender-combined sample. In stage II in silico replication (two cohorts), FGFRL1 rs4647940 was the only signal marginally replicated for FN-BMD (P = 5.08 × 10(-3)) at α = 0.10/11 = 9.09 × 10(-3). PRR5 rs3213550 was also selected based on biological significance. In stage III de novo genotyping replication (two cohorts), FGFRL1 rs4647940 was the only signal significantly replicated for FN-BMD (P = 7.55 × 10(-6)) at α = 0.05/2 = 0.025 in gender-combined sample. Aggregating three stages, FGFRL1 rs4647940 was the single stage I-discovered and stages II- and III-replicated signal attaining GWS for FN-BMD (P = 8.87 × 10(-12)). Dual-luciferase reporter assays demonstrated that FGFRL1 3' untranslated region harboring rs4647940 appears to be hsa-miR-140-5p's target site. In a zebrafish microinjection experiment, dre-miR-140-5p is shown to exert a dramatic impact on craniofacial skeleton formation. Taken together, we provided functional evidence for a novel FGFRL1 poly-miRTS rs4647940 in a previously known 4p16.3 locus, and experimental and clinical genetics studies have shown both FGFRL1 and hsa-miR-140-5p are important for bone formation.

Abdominal Aortic Calcification Identified on Lateral Spine Images From Bone Densitometers Are a Marker of Generalized Atherosclerosis in Elderly Women.

OBJECTIVE: Dual-energy x-ray absorptiometry is a low-cost, minimal radiation technique used to improve fracture prediction. Dual-energy x-ray absorptiometry machines can also capture single-energy lateral spine images, and abdominal aortic calcification (AAC) is commonly seen on these images. APPROACH AND RESULTS: We investigated whether dual-energy x-ray absorptiometry-derived measures of AAC were related to an established test of generalized atherosclerosis in 892 elderly white women aged >70 years with images captured during bone density testing in 1998/1999 and B-mode carotid ultrasound in 2001. AAC scores were calculated using a validated 24-point scale into low (AAC24 score, 0 or 1), moderate (AAC24 scores, 2-5), and severe AAC (AAC24 scores, >5) seen in 45%, 36%, and 19%, respectively. AAC24 scores were correlated with mean and maximum common carotid artery intimal medial thickness (rs=0.12, P<0.001 and rs=0.14, P<0.001). Compared with individuals with low AAC, those with moderate or severe calcification were more likely to have carotid atherosclerotic plaque (adjusted prevalence ratio (PR), 1.35; 95% confidence interval, 1.14-1.61; P<0.001 and prevalence ratio, 1.94; 95% confidence interval, 1.65-2.32; P<0.001, respectively) and moderate carotid stenosis (adjusted prevalence ratio, 2.22; 95% confidence interval, 1.39-3.54; P=0.001 and adjusted prevalence ratio, 4.82; 95% confidence interval, 3.09-7.050; P<0.001, respectively). The addition of AAC24 scores to traditional risk factors improved identification of women with carotid atherosclerosis as quantified by C-statistic (+0.075, P<0.001), net reclassification (0.249, P<0.001), and integrated discrimination (0.065, P<0.001). CONCLUSIONS: AAC identified on images from a dual-energy x-ray absorptiometry machine were strongly related to carotid ultrasound measures of atherosclerosis. This low-cost, minimal radiation technique used widely for osteoporosis screening is a promising marker of generalized extracoronary atherosclerosis.

Dietary inflammatory index in relation to sub-clinical atherosclerosis and atherosclerotic vascular disease mortality in older women.

Arterial wall thickening, stimulated by low-grade systemic inflammation, underlies many cardiovascular events. As diet is a significant moderator of systemic inflammation, the dietary inflammatory index (DIITM) has recently been devised to assess the overall inflammatory potential of an individual's diet. The primary objective of this study was to assess the association of the DII with common carotid artery-intima-media thickness (CCA-IMT) and carotid plaques. To substantiate the clinical importance of these findings we assessed the relationship of DII score with atherosclerotic vascular disease (ASVD)-related mortality, ischaemic cerebrovascular disease (CVA)-related mortality and ischaemic heart disease (IHD)-related mortality more. The study was conducted in Western Australian women aged over 70 years (n 1304). Dietary data derived from a validated FFQ (completed at baseline) were used to calculate a DII score for each individual. In multivariable-adjusted models, DII scores were associated with sub-clinical atherosclerosis: a 1 sd (2·13 units) higher DII score was associated with a 0·013-mm higher mean CCA-IMT (P=0·016) and a 0·016-mm higher maximum CCA-IMT (P=0·008), measured at 36 months. No relationship was seen between DII score and carotid plaque severity. There were 269 deaths during follow-up. High DII scores were positively associated with ASVD-related death (per sd, hazard ratio (HR): 1·36; 95 % CI 1·15, 1·60), CVA-related death (per sd, HR: 1·30; 95 % CI 1·00, 1·69) and IHD-related death (per sd, HR: 1·40; 95 % CI 1·13, 1·75). These results support the hypothesis that a pro-inflammatory diet increases systemic inflammation leading to development and progression of atherosclerosis and eventual ASVD-related death.

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density.

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.