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Shea M.K.,Sticht Center on Aging | Booth S.L.,Tufts University | Cushman M.,University of Vermont | Tracy R.P.,University of Vermont | Kritchevsky S.B.,Sticht Center on Aging
American Journal of Clinical Nutrition | Year: 2013

Background: Animal studies have shown that vitamin K treatment reduced vascular calcification, but human data are limited. Objective: We determined the association between vitamin K status and coronary artery calcium (CAC) progression in the Multi-Ethnic Study of Atherosclerosis by using a case-cohort design. Design: Serum phylloquinone (vitamin K1) was measured in 296 participants with extreme CAC progression and 561 randomly selected participants without extreme CAC progression; all subjects had baseline and follow-up CAC measures (mean follow-up: 2.5 y). A serum vitamin K1 concentration was considered low at <1.0 nmol/L (the distribution median). Outcomes were replicated by using post hoc per-protocol analyses of a vitamin K1 supplementation trial. Results: The OR (95% CI) for extreme CAC progression for subjects with low serum vitamin K1 compared with subjects without extreme CAC progression was 1.34 (0.94, 1.90; NS) when adjusted for demographics and confounders. A significant interaction between low vitamin K1 and antihypertension medication use was detected (P = 0.016). Hypertension medication users with low serum vitamin K1 were more likely to have extreme CAC progression than were medication users without extreme CAC progression [OR (95% CI): 2.37 (1.38, 4.09)]. In replication, baseline antihypertensive medication users in the supplementation group had less CAC progression than did those in the control group [adjusted mean ± SEM of the 3-y CAC change was +5 ± 20 Agatston units (AU) in the vitamin K1 group (n = 40) and +44 ± 13 AU in the placebo group (n = 49); P < 0.01]. Conclusions: Although the point estimate of our primary analysis suggests low serum vitamin K1 is associated with greater CAC progression, the difference was NS. Low serum vitamin K1 was significantly associated with CAC progression in antihypertension medication users, which, to our knowledge, is a novel finding conditionally replicated by using an independent sample. Intervention trials are needed to determine whether improving serum vitamin K1 reduces CAC progression, especially in hypertensive individuals. This trial was registered at clinicaltrials.gov as NCT00183001. Copyright © 2013 American Society for Nutrition.

Shea M.K.,Tufts University | Cushman M.,University of Vermont | Booth S.L.,Tufts University | Kritchevsky S.B.,Sticht Center on Aging
Thrombosis and Haemostasis | Year: 2014

Vitamin K is integral to haemostatic function, and in vitro and animal experiments suggest that vitamin K can suppress production of inflammatory cytokines. To test the hypothesis that higher vitamin K status is associated with lower haemostatic activation and inflammation in community-dwelling adults, we analysed the cross-sectional association between serum phylloquinone (vitamin K1) with haemostatic and inflammatory biomarkers in 662 participants in the MultiEthnic Study of Atherosclerosis (MESA) [mean (SD) age=62 (10) years; 46% female; 37% Caucasian, 25% African-American, 25% Hispanic, 13% Chinese-American]. Following adjustment for demographic and lifestyle characteristics, medication use, triglycerides and body mass index, those in the highest quartile of serum phylloquinone had significantly lower circulating interleukin-6 [adjusted mean (SEM) pmol/l: quartile 4 (Q4)=1.22 (0.07), quartile 1 (Q1)=1.45 (0.07); p-trend<0.01], C-reactive protein [adjusted mean (SEM) mg/dl: Q4=1.57 (0.11), Q1=2.08 (0.18); p-trend=0.02], soluble intercellular adhesion molecule-1 [adjusted mean (SEM) ng/ml: Q4=247 (11), Q1=288 (11); p-trend=0.02], and plasmin-antiplasmin complex [adjusted mean (SEM) nmol/l: Q4=4.02 (0.1), Q1=4.31 (0.1), p-trend=0.04]. We detected an interaction between age and serum phylloquinone with respect to factor VIII and D-dimer (interaction p-values=0.03 and 0.09, respectively). Among participants ≥70 years, serum phylloquinone was inversely associated with factor VIII activity (p-trend=0.06) and positively associated with D-dimer (p-trend=0.01), but was not associated with either marker among participants <70 years (both p≥0.38). In contrast, dietary phylloquinone intake was not associated with any inflammatory or haemostatic biomarker evaluated (all p-trend>0.11). These findings are consistent with laboratorybased studies that suggest a possible anti-inflammatory role for vitamin K. Whether or not these associations predict clinical outcomes linked to elevated inflammation or haemostatic activation remains to be determined. © Schattauer 2014.

Wright J.T.,Case Western Reserve University | Williamson J.D.,Sticht Center on Aging | Whelton P.K.,Tulane University | Snyder J.K.,U.S. National Institutes of Health | And 13 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. METHODS We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. RESULTS At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensivetreatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensivetreatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensivetreatment group than in the standard-treatment group. CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. © 2015 Massachusetts Medical Society.

Beavers K.M.,Sticht Center on Aging | Beavers D.P.,Sticht Center on Aging | Harris T.B.,University of Pittsburgh | Hue T.F.,U.S. National Institute on Aging | And 7 more authors.
American Journal of Clinical Nutrition | Year: 2013

Background: In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline. Objective: We assessed the association between several measures of body composition and age-related decline in gait speed. Design: Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed-effects models. Results: Gait speed declined by 0.06 6 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gaitspeed decline (6SE) in both men and women (20.01 6 0.00 and 20.02 6 0.00 m/s per 0.57 cm2, respectively; P < 0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm2 increase in thigh intermuscular fat was associated with a 0.01 6 0.00-m/s decrease in gait speed, whereas every 16.92-cm2 decrease in thigh muscle was associated with a 0.01 6 0.00-m/s decrease in gait speed. Conclusions: High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed. © 2013 American Society for Nutrition.

Feng X.,Medical Center Boulevard | Todd T.,Medical Center Boulevard | Lintzenich C.R.,Medical Center Boulevard | Ding J.,Section on Gerontology and Geriatric Medicine | And 3 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2013

Background. Age-related muscle weakness due to atrophy and fatty infiltration in orofacial muscles may be related to swallowing deficits in older adults. An important component of safe swallowing is the geniohyoid (GH) muscle, which helps elevate and stabilize the hyoid bone, thus protecting the airway. This study aimed to explore whether aging and aspiration in older adults were related to GH muscle atrophy and fatty infiltration.Method. Eighty computed tomography scans of the head and neck from 40 healthy older (average age 78 years) and 40 younger adults (average age 32 years) were analyzed. Twenty aspirators and 20 nonaspirators from the 40 older adults had been identified previously. Two-dimensional views in the sagittal and coronal planes were used to measure the GH cross-sectional area and fatty infiltration.Results. GH cross-sectional area was larger in men than in women (p <. 05). Decreased cross-sectional area was associated with aging (p <. 05), and cross-sectional area was significantly smaller in aspirators compared with nonaspirators, but only among the older men (p <. 01). Increasing fatty infiltration was associated with aging in the middle (p <. 05) and posterior (p <. 01) portions of the GH muscle. There was no significant difference in fatty infiltration of the GH muscle among aspirators and nonaspirators.Conclusion. GH muscle atrophy was associated with aging and aspiration. Fatty infiltration in the GH muscle was increased with aging but not related to aspiration status. These findings suggest that GH muscle atrophy may be a component of decreased swallowing safety and aspiration in older adults and warrants further investigation. © 2012 © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Bolandzadeh N.,University of British Columbia | Liu-Ambrose T.,University of British Columbia | Aizenstein H.,University of Pittsburgh | Harris T.,U.S. National Institute on Aging | And 5 more authors.
NeuroImage | Year: 2014

Importance: Cerebral white matter hyperintensities (WMHs) are involved in the evolution of impaired mobility and executive functions. Executive functions and mobility are also associated. Thus, WMHs may impair mobility directly, by disrupting mobility-related circuits, or indirectly, by disrupting circuits responsible for executive functions. Understanding the mechanisms underlying impaired mobility in late life will increase our capacity to develop effective interventions. Objective: To identify regional WMHs most related to slower gait and to examine whether these regional WMHs directly impact mobility, or indirectly by executive functions. Design: Cross-sectional study. Twenty-one WMH variables (i.e., total WMH volume and WMHs in 20 tracts), gait speed, global cognition (Modified Mini-Mental State Examination; 3MS), and executive functions and processing speed (Digit-Symbol Substitution Test; DSST) were assessed. An L1-L2 regularized regression (i.e., Elastic Net model) identified the WMH variables most related to slower gait. Multivariable linear regression models quantified the association between these WMH variables and gait speed. Formal tests of mediation were also conducted. Setting: Community-based sample. Participants: Two hundred fifty-three adults (mean age: 83. years, 58% women, 41% black). Main Outcome Measure: Gait speed. Results: In older adults with an average gait speed of 0.91. m/sec, total WMH volume, WMHs located in the right anterior thalamic radiation (ATRR) and frontal corpus. callosum (CCF) were most associated with slower gait. There was a >. 10% slower gait for each standard deviation of WMH in CCF, ATRR or total brain (standardized beta in m/sec [. p value]: -. 0.11 [. p= 0.046], -. 0.15 [. p= 0.007] and -. 0.14 [. p= 0.010], respectively). These associations were substantially and significantly attenuated after adjustment for DSST. This effect was stronger for WMH in CCF than for ATRR or total WMH (standardized beta in m/sec [. p value]: -. 0.07 [. p= 0.190], -. 0.12 [. p= 0.024] and -. 0.10 [. p= 0.049], respectively). Adjustment for 3MS did not change these associations. The mediation analyses also found that DSST significantly mediated the associations between WMHs and gait speed. Our models were adjusted for age, sex, BMI, quadriceps strength, years of education, standing height, and prevalent hypertension. Conclusion: The impact, direct or indirect, of WMHs on gait speed depended on their location and was mediated by executive function. Thus, multi-faceted interventions targeting executive control functions as well as motor functions, such as balance and strength training, are candidates to the maintenance of mobility across the lifespan. © 2014 Elsevier Inc.

Murphy R.A.,U.S. National Institute on Aging | Reinders I.,U.S. National Institute on Aging | Register T.C.,Sticht Center on Aging | Ayonayon H.N.,University of California at San Francisco | And 6 more authors.
American Journal of Clinical Nutrition | Year: 2014

Background: Obesity is a risk factor for disability, but risk of specific adipose depots is not completely understood. Objective: We investigated associations between mobility limitation, performance, and the following adipose measures: body mass index (BMI) and areas and densities of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) in older adults. Design: This was a prospective population-based study of men (n = 1459) and women (n = 1552) initially aged 70-79 y and free from mobility limitation. BMI was determined from measured height and weight. Adipose tissue area and density in Hounsfield units were measured in the thigh and abdomen by using computed tomography. Mobility limitation was defined as 2 consecutive reports of difficulty walking one-quarter mile or climbing 10 steps during semiannual assessments over 13 y. Poor performance was defined as a gait speed ,1 m/s after 9 y of follow-up (n = 1542). Results: In models adjusted for disability risk factors, BMI, and areas of VAT, abdominal SAT, and IMAT were positively associated with mobility limitation in men and women. In women, thigh SAT area was positively associated with mobility limitation risk, whereas VAT density was inversely associated. Associations were similar for poor performance. BMI and thigh IMAT area (independent of BMI) were particularly strong indicators of incident mobility limitation and poor performance. For example, in women, the HR (95% CI) and OR (95% CI) associated with an SD increment in BMI for mobility limitation and poor performance were 1.31 (1.21, 1.42) and 1.41 (1.13, 1.76), respectively. In men, the HR (95% CI) and OR (95% CI) associated with an SD increment in thigh IMAT for mobility limitation and poor performance were 1.37 (1.27, 1.47) and 1.54 (1.18, 2.02), respectively. Conclusions: Even into old age, higher BMI is associated with mobility limitation and poor performance. The amount of adipose tissue in abdominal and thigh depots may also convey risk beyond BMI. © 2014 American Society for Nutrition.

Xiao Q.,U.S. National Cancer Institute | Murphy R.A.,U.S. National Institute on Aging | Houston D.K.,Sticht Center on Aging | Harris T.B.,U.S. National Institute on Aging | And 2 more authors.
JAMA Internal Medicine | Year: 2013

Importance: Calcium intake has been promoted because of its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health. Objective: To investigate whether intake of dietary and supplemental calcium is associated with mortality from total cardiovascular disease (CVD), heart disease, and cerebrovascular diseases. Design and Setting: Prospective study from 1995 through 1996 in California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania and the 2 metropolitan areas of Atlanta, Georgia, and Detroit, Michigan. Participants: A total of 388 229 men and women aged 50 to 71 years from the National Institutes of Health- AARP Diet and Health Study. Main Outcome Measures: Dietary and supplemental calcium intake was assessed at baseline (1995- 1996). Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease deaths were ascertained using the National Death Index. Multivariate Cox proportional hazards regression models adjusted for demographic, lifestyle, and dietary variables were used to estimate relative risks (RRs) and 95% CIs. Results: During a mean of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death (RR1000 vs 0 mg/d, 1.20; 95% CI, 1.05- 1.36), more specifically with heart disease death (RR, 1.19; 95% CI, 1.03-1.37) but not significantly with cerebrovascular disease death (RR,1.14; 95% CI, 0.81-1.61). In women, supplemental calcium intake was not associated with CVD death (RR, 1.06; 95% CI, 0.96-1.18), heart disease death (1.05; 0.93-1.18), or cerebrovascular disease death (1.08; 0.87-1.33). Dietary calcium intake was unrelated to CVD death in either men or women. Conclusions and Relevance: Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD death in men but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health. © 2013 American Medical Association.

McAuley P.A.,Winston-Salem State University | Beavers K.M.,Sticht Center on Aging
Progress in Cardiovascular Diseases | Year: 2014

Until recently, cardiorespiratory fitness (CRF) has been overlooked as a potential modifier of the inverse association between obesity and mortality (the so-called obesity paradox), observed in patients with known or suspected cardiovascular (CV) disease. Evidence from five observational cohort studies of 30,104 patients (87% male) with CV disease indicates that CRF significantly alters the obesity paradox. There is general agreement across studies that the obesity paradox persists among patients with low CRF, regardless of whether adiposity is assessed by body mass index, waist circumference, or percentage body fat. However, among patients with high CRF, risk of all-cause mortality is lowest for the overweight category in some, but not all, studies, suggesting that higher levels of fitness may modify the relationship between body fatness and survival in patients manifesting an obesity paradox. Further study is needed to better characterize the joint contribution of CRF and obesity on mortality in diverse populations. © 2014 Elsevier Inc.

Kyla Shea M.,Sticht Center on Aging | Holden R.M.,Queen's University
Advances in Nutrition | Year: 2012

Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients. © 2012 American Society for Nutrition.

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