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Background: Patients with rheumatoid arthritis (RA) have double the risk of cardiovascular (CV) events and greater extent of coronary artery calcium (CAC) compared to the general population. Antibodies to citrullinated protein antigens (ACPA) have been linked to CAC in patients with RA; and RA-related autoimmunity has been associated with CAC in Black women without RA. ACPA are detectable years before RA onset and in some individuals who do not develop RA. Given the association between vascular calcification and CV events in the general population, we investigated associations between ACPA and coronary and abdominal aorta calcification (AAC). Methods: In a randomly selected subset of 1968 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), we measured ACPA using a multiplex array of 28 different ACPA. Each ACPA was defined as positive if >95 th percentile cut-off in MESA. The number of (+) ACPA were summed for each participant (range 0-28). We measured AAC and CAC using computed tomography scans. We evaluated associations between number of ACPA, individual ACPA and AAC and CAC using multivariable linear regression, adjusting for covariates and testing for interactions with gender and race/ethnicity. Results: Among 1828 MESA participants with complete data, average age was 65(10); were 50% female, 40% White, 13% Chinese, 21% Black, 26% Hispanic/Latino and 27% positive (+) for at least one ACPA. Among ACPA(+) participants, median number of ACPA was 1 (1, 6) and ranged from 1-28 ACPA. Number of ACPA was neither significantly associated with CAC severity (p=0.06) nor AAC severity (p=0.48). These associations did not differ by gender or race. However, several individual ACPA were associated with CAC and AAC. In particular, for every SD higher citrullinated ApoA antibody concentration (anti-cit-ApoA), CAC severity was 0.15 (0.07)% higher (p=0.03); and AAC severity was 0.07 (0.04) % lower (p=0.08) in fully adjusted analysis. Associations between anti-cit-ApoA and AAC severity were modified by gender (p interaction =0.02), where in women for every SD higher anti-cit-ApoA, AAC severity was 0.15 (0.06)% lower (p=0.007); and in men, AAC severity was 0.03 (0.05)% higher, although this association was not statistically significant (p=0.55). For every SD higher citrullinated Fibrinogen antibody (anti-cit-Fibrinogen) concentration, CAC severity was 0.14 (0.07) % higher (p=0.05); and AAC severity was 0.10 (0.04) % lower (p=0.01) in fully adjusted analysis. There was no significant interaction between anti-cit-Fibrinogen and gender or race. Conclusion: In a community-dwelling population without RA, ACPA were associated with higher CAC severity and lower AAC severity, independent of traditional CV risk factors. Because we did not expect the inverse association between ACPA and AAC severity, continued research is needed to better understand mechanisms explaining this association.

ObjectivesThe purpose of this study was to measure the indices of radiographic developmental dysplasia of the hip (DDH) in a cross-sectional study of an elderly Japanese population.MethodsHip radiographs of 427 informed, voluntary Japanese community-dwelling individuals (279 female and 148 male) aged 50–96 years-old were obtained from Miyagawa village in Japan through a health screening. The hip radiographs were measured by a custom-written, semi-automated MATLAB program. The center edge (CE) angle, acetabular roof obliquity (ARO), acetabular head index (AHI), and minimum joint space width (mJSW) were measured. We examined the associations between gender, side-of-hip, and age group on radiographic DDH and hip osteoarthritis (OA).ResultsThe mean CE angle was 31.0°. The mean ARO was 5.8°. The mean AHI was 88.2%. The mean mJSW was 4.0 mm. Of the total population, 29.9% had DDH and 4.0% had hip OA. Of those who had hip OA, 41.2% were secondary OA, and 58.8% were primary OA. The relationship between DDH and OA was not significant.ConclusionDDH is unlikely to be an important cause of hip OA in the present population-based study.

Low vertebral bone mass is a major risk factor for vertebral compression fractures. While sarcopenia has been shown to be associated with low bone mineral density (BMD), it is not known whether trunk musculature is directly associated with lumbar BMD, and whether exercise modifies this association. Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we sought to determine the association of muscle density and fat fraction of the psoas, paraspinal, and oblique muscle groups with L3 lumbar volumetric BMD, and whether these associations were modified by exercise. We obtained L3 vBMD measurements, and fat and muscle measurements (in Hounsfield units (HU)) from abdominal CT scans spanning L2-L4 intervertebral disc spaces. Muscle density was defined as the mean HU value for a muscle group area. Fat fraction was calculated as the mean HU value for the muscle group fat area/total muscle group area(sq cm). Exercise data were self-reported (MET-min/wk). We utilized multivariable linear regression to evaluate these associations, stratified by gender, and adjusting for demographics, BMI, smoking status, impaired fasting glucose, and corticosteroid and anti-resorptive medication use. Among 1923 MESA participants, mean age was 62±10, 49% were female, 40% White, 21% Black, 26% Hispanic/Latino and 13% Chinese. In fully adjusted analysis, for every 1 SD higher psoas fat fraction, there was a 3.19 SD lower L3 vBMD in men and 4.3 SD lower SD L3 vBMD in women (p

Introduction: Individuals with antibodies to citrullinated protein antigens (ACPA) have higher risk for cardiovascular disease (CVD). Cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα), have been identified as pro-atherogenic. While the association between ACPA and cytokines has been studied in rheumatoid diseases, it has not been studied in the general population. We hypothesized that ACPA are positively associated with IL-6, c-reactive protein (CRP), and TNFα; and that gender and race/ethnicity modify this association. Methods: In 1743 Multi-Ethnic Study of Atherosclerosis participants without clinical CVD, we evaluated the association between number of ACPA and IL-6, CRP, and TNFα using multivariable linear regression. We adjusted for demographics, CVD risk factors, and medication use; and tested for interactions by gender and race/ethnicity. ACPA was measured as an array of 38 individual ACPA with the cut-off for positivity for each antibody set at the 95 th percentile. CRP, IL-6, and TNFα were measured in serum of fasting participants; values were log-transformed to reduce skewness. Results: Average age was 64.7±9.7 years; 50% were women, 40% Caucasian, 13% Chinese American, 21% African American, and 26% Hispanic American. Approximately 31% (537) had at least one positive ACPA. In the fully adjusted analysis, each additional ACPA was associated with 0.3±0.1% (p=0.005) higher serum IL-6 and 0.6±0.2% (p=0.007) higher CRP. ACPA was not associated with TNFα. Associations of ACPA with CRP were modified by gender (p interaction = 0.000) and race/ethnicity (p interaction = 0.000). In men, each additional ACPA was associated with 0.4±0.1% (p=0.015) higher IL-6 and 0.7±0.2% (p=0.007) higher CRP. In women, this association was not observed. In Hispanic participants, each additional ACPA was associated with 0.3±0.2% (p=0.049) higher IL-6 and 0.8±0.3% (p=0.010) higher CRP; in Caucasian participants, each additional ACPA was associated with 0.4±0.2% (p=0.014) higher IL-6 and 0.6±0.3% (p=0.026) higher CRP. This association was not observed in Chinese or African American participants. Conclusion: In a multi-ethnic community-dwelling population, higher number of ACPA was associated with higher IL-6 and CRP.

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH)2 D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D-binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR)

While obesity and insulin resistance are known risk factors for wound complications after total joint arthroplasty (TJA), the biologic causes remain to be elucidated. Recently, neutrophil extracellular trap formation (NETosis) was identified as a mediator of delayed wound healing in insulin resistant states. Herein, we explored the relationship between obesity, insulin resistance and biomarkers of NET formation in TJA subjects. We enrolled 14 obese (body mass index [BMI]≥30 kg/m2), and 15 lean (BMI2) subjects undergoing primary knee or hip TJA. On the day of surgery, skeletal muscle proximal to the operated joint and plasma were collected. Protein abundance of NETosis biomarkers, peptidylarginine deaminase 4 (PAD4) and neutrophil elastase (NE) were assessed in skeletal muscle by immunoblotting and metabolic parameters (glucose, insulin, triglycerides, free fatty acids) and cell-free double-stranded DNA (cf-dsDNA) were assessed in plasma and were correlated with obesity and insulin resistance (as measured by the homeostatic model assessment for insulin resistance). When comparing lean and obese subjects, there were no significant differences in plasma cf-dsDNA or skeletal muscle NE or PAD4 abundance. In contrast, skeletal muscle PAD4 abundance, but not NE or plasma cf-dsDNA, was positively correlated with insulin resistance. Compared to insulin sensitive subjects, insulin resistant TJA subjects have higher expression of PAD4 at the surgical site and therefore may have higher rates of NET formation, which may lead to delayed surgical site wound healing.

Background Obesity is prevalent among patients undergoing total hip arthroplasty and has been associated with the risk of wound complications, particularly when an anterior approach is used. However, most studies have focused on obesity defined by the body mass index (BMI), without considering the metabolic effects of adiposity. Thus, in this study, we investigated the independent effects of the BMI and metabolic syndrome on wound complications after total hip arthroplasty. Methods Among 804 consecutive patients undergoing total hip arthroplasty between October 2013 and July 2016, we evaluated the associations between obesity (BMI ≥30 mg/kg2), metabolic syndrome (defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines), and wound complication (defined as documented wound dehiscence, drainage, erythema, hematoma, infection, or seroma) over a 1-year follow-up period. We used Cox proportional hazards models adjusting for demographics, smoking status, and hospital length of stay. Results Patients’ mean age at time of surgery was 62.0 ± 11.9 years. Forty-seven percent were male, 27.9% were obese, and 11.6% met the definition for metabolic syndrome. Metabolic syndrome was associated with a 4-fold higher risk of wound complication (95% confidence interval: 1.4-11.1) after adjusting for all covariates including the BMI. In unadjusted analysis, obesity was associated with a higher risk of wound complication (hazard ratio: 2.8, 95% confidence interval: 1.3-6.2). However, obesity was not associated with the risk of wound complication after adjusting for the metabolic syndrome (P = .16). Conclusions Metabolic syndrome, but not obesity, defined by a BMI ≥30, was associated with wound complications, suggesting that metabolic effects of adiposity may represent a distinct risk factor in the development of wound complications from a higher BMI alone.

BackgroundPhysical activity (PA) in pre-clinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. Yet, PA in RA patients is less than in counterparts without RA, which can be attributed partly to symptoms of inflammatory arthritis. Therefore, we investigated whether joint swelling, stiffness, or pain were associated with PA in first-degree relatives (FDRs) of RA patients, a population at higher risk for future RA.MethodsWe evaluated associations of joint stiffness, joint swelling, and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain. PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking, and RA-related autoantibodies.ResultsAverage weighted PA time was 37±7 hours. In cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (pinteraction=0.0002, pinteraction=0.002), and joint swelling was associated with higher PA time (pinteractionConclusionBaseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.

Background We sought to identify biomarkers that indicate low turnover on bone histomorphometry in chronic kidney disease (CKD) patients, and subsequently determined whether this panel identified differential risk for fractures in community-dwelling older adults. Methods Among CKD patients who underwent iliac crest bone biopsies and histomorphometry, we evaluated candidate biomarkers to differentiate low turnover from other bone disease. We applied this biomarker panel to 641 participants in the Health Aging and Body Composition Study (Health ABC) study with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 who were followed for fracture. Cox proportional hazards models evaluated the association of bone mineral density (BMD) with fracture risk and determined whether biomarker-defined low bone turnover modified fracture risk at any level of BMD. Results In 39 CKD patients age 64 ± 13 years, 85% female, with mean eGFR 37 ± 14 mL/min/1.73 m2 who underwent bone biopsy, lower fibroblast growth factor (FGF)-23, higher ɑ-Klotho, and lower parathyroid hormone (PTH) indicated low bone turnover in accordance with bone histomorphometry parameters (individual area under the curve = 0.62, 0.73, and 0.55 respectively; sensitivity = 22%, specificity = 100%). In Health ABC, 641 participants with CKD were age 75 ± 3 years , 49% female, with mean eGFR 48 ± 10 mL/min/1.73 m2. For every SD lower hip BMD at baseline, there was an 8-fold higher fracture risk in individuals with biomarker-defined low turnover (hazard ratio 8.10 [95% CI, 3.40-19.30]) vs a 2-fold higher risk in the remaining individuals (hazard ratio 2.28 [95% CI, 1.69-3.08]) (Pinteraction = .082). Conclusions In CKD patients who underwent bone biopsy, lower FGF-23, higher ɑ-Klotho, and lower PTH together had high specificity for identifying low bone turnover. When applied to older individuals with CKD, BMD was more strongly associated with fracture risk in those with biomarker-defined low turnover.

ObjectivesRecently, the density score of coronary artery calcium (CAC) has been shown to be associated with a lower risk of cardiovascular disease (CVD) events at any level of CAC volume. Whether risk factors for CAC volume and CAC density are similar or distinct is unknown. We sought to evaluate the associations of CVD risk factors with CAC volume and CAC density scores.MethodsBaseline measurements from 6814 participants free of clinical CVD were collected for the Multi-Ethnic Study of Atherosclerosis. Participants with detectable CAC (n=3398) were evaluated for this study. Multivariable linear regression models were used to evaluate independent associations of CVD risk factors with CAC volume and CAC density scores.ResultsWhereas most CVD risk factors were associated with higher CAC volume scores, many risk factors were associated with lower CAC density scores. For example, diabetes was associated with a higher natural logarithm (ln) transformed CAC volume score (standardised β=0.44 (95% CI 0.31 to 0.58) ln-units) but a lower CAC density score (β=−0.07 (−0.12 to −0.02) density units). Chinese, African-American and Hispanic race/ethnicity were each associated with lower ln CAC volume scores (β=−0.62 (−0.83to −0.41), −0.52 (−0.64 to −0.39) and −0.40 (−0.55 to −0.26) ln-units, respectively) and higher CAC density scores (β= 0.41 (0.34 to 0.47), 0.18 (0.12 to 0.23) and 0.21 (0.15 to 0.26) density units, respectively) relative to non-Hispanic White.ConclusionsIn a cohort free of clinical CVD, CVD risk factors are differentially associated with CAC volume and density scores, with many CVD risk factors inversely associated with the CAC density score after controlling for the CAC volume score. These findings suggest complex associations between CVD risk factors and these components of CAC.

Author(s): Shahidi, Bahar; Parra, Callan L; Berry, David B; Hubbard, James C; Gombatto, Sara; Zlomislic, Vinko; Allen, R Todd; Hughes-Austin, Jan; Garfin, Steven; Ward, Samuel R | Abstract: Study designRetrospective chart analysis of 199 individuals aged 18 to 80 years scheduled for lumbar spine surgery.ObjectiveThe purpose of this study was to quantify changes in muscle cross-sectional area (CSA) and fat signal fraction (FSF) with age in men and women with lumbar spine pathology and compare them to published normative data.Summary of background dataPathological changes in lumbar paraspinal muscle are often confounded by age-related decline in muscle size (CSA) and quality (fatty infiltration). Individuals with pathology have been shown to have decreased CSA and fatty infiltration of both the multifidus and erector spinae muscles, but the magnitude of these changes in the context of normal aging is unknown.MethodsIndividuals aged 18 to 80 years who were scheduled for lumbar surgery for diagnoses associated with lumbar spine pain or pathology were included. Muscle CSA and FSF of the multifidus and erector spinae were measured from preoperative T2-weighted magnetic resonance images at the L4 level. Univariate and multiple linear regression analyses were performed for each outcome using age and sex as predictor variables. Statistical comparisons of univariate regression parameters (slope and intercept) to published normative data were also performed.ResultsThere was no change in CSA with age in either sex (P g 0.05), but women had lower CSAs than men in both muscles (P l 0.0001). There was an increase in FSF with age in erector spinae and multifidus muscles in both sexes (P l 0.0001). Multifidus FSF values were higher in women with lumbar spine pathology than published values for healthy controls (P = 0.03), and slopes tended to be steeper with pathology for both muscles in women (P l 0.08) but not in men (P g 0.31).ConclusionLumbar muscle fat content, but not CSA, changes with age in individuals with pathology. In women, this increase is more profound than age-related increases in healthy individuals.Level of evidence3.

Background Kidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown. Study Design Case-cohort study. Setting & Participants The FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257). Predictor Using spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α 1 -microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide). Outcome Death-censored allograft failure. Results In models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure. Limitations We lack kidney biopsy data, BK titers, and HLA antibody status. Conclusions Urine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR.

Background and objectives Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR Design, setting, participants, & measurements Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000–2002 in the MESA and 1989–1993 in the CHS), we investigated associations between serum potassium categories ( Results Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction Conclusions Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.

BackgroundIliac crest bone biopsy with histomorphometry is the gold standard for diagnosis of abnormalities in bone turnover, yet fractures more frequently occur at the greater trochanter of the hip. Whether bone turnover is similar at these two anatomic sites within individuals is uncertain.MethodsWe collected bone biopsy samples from the ipsilateral iliac crest and greater trochanter in 9 deceased individuals undergoing autopsies at an academic medical center between March-August 2018. We measured 14 static bone histomorphometry parameters including osteoclast number (N.Oc/T.A), eroded surface (ES/BS), trabecular separation (Tb.Sp), osteoclast surface (Oc.S/BS) and osteoid volume (OV/BV) as markers of bone turnover, mineralization, and volume (TMV), and evaluated the correlation of these markers between the iliac crest and greater trochanter.ResultsAverage age at time of death was 58±15years, 2 were women, and average time from death to autopsy was 2.9±1.8days. Overall, correlations of the markers of bone turnover across the two sites were poor, ranging from as low as 0 for Tb.Sp (p=1.0) to as high as 0.583 for Oc.S/BS (p=0.102).ConclusionsStatic histomorphometric measures of bone turnover at the iliac crest may not provide reliable information about turnover at other anatomic sites.

Background The relationship between lumbar spine posture and muscle structure is not well understood. Objectives To investigate the predictive capacity of muscle structure on lumbar spine posture in active-duty Marines. Methods Forty-three Marines were scanned in this cross-sectional study, using an upright magnetic resonance imaging scanner while standing without load and standing, sitting, and prone on elbows with body armor. Cobb, horizontal, and sacral angles were measured. Marines were then scanned while unloaded in supine using a supine magnetic resonance imaging scanner. The imaging protocol consisted of T2 intervertebral disc mapping; high-resolution, anatomical, fat-water separation, and diffusion tensor imaging to quantify disc hydration and muscle volume, fat fraction, and restricted diffusion profiles in the lumbar muscles. A stepwise multiple linear regression model was used to identify physiological measures predictive of lumbar spine posture. Results The multiple regression model demonstrated that fractional anisotropy of the erector spinae was a significant predictor of lumbar posture for 7 of 18 dependent variables measured, and explained 20% to 35% of the variance in each model. Decreased fractional anisotropy of the erector spinae predicted decreased lordosis, lumbosacral extension, and anterior pelvic tilt. Conclusion Fractional anisotropy is inversely related with muscle fiber size, which is associated with the isometric force-generating capacity of a muscle fiber. This suggests that stronger erector spinae muscles predict decreased lordosis, lumbosacral extension, and anterior pelvic tilt in a highly trained population. J Orthop Sports Phys Ther 2018;48(8):613-621. Epub 17 May 2018. doi:10.2519/jospt.2018.7865.

Background: Antibodies to citrullinated proteins (ACPA) are elevated in patients with rheumatoid arthritis (RA) and have been linked to altered left ventricular (LV) structure and function in RA. ACPA are detectable years before RA onset and in some individuals who do not develop RA. Among individuals without RA and without heart failure in MESA, we investigated associations between ACPA, LV mass, and LV ejection fraction (LVEF). Methods: In a cross-sectional subsample of 1232 MESA participants, we measured ACPA using a multiplex array of 38 different ACPA. Each ACPA was defined as positive (+) if > 95 th percentile cut-off in MESA. Number of (+) ACPA were summed for each participant (range 0-38). We compared ACPA(-) to ACPA(+) participants, and examined the association of number of ACPA with both outcomes. LVmass (g) and LVEF (%) were measured on cardiac MRI. We analyzed associations using generalized linear regression and adjusted for covariates listed in the table. Results: Mean age was 65 years. The sample was 50% women, 40% Caucasian; and 31% had ≥ 1 (+) ACPA. Among ACPA(+) participants, median number (+) was 2 (IQR 1-6). ACPA(+) participants were similar to ACPA(-) participants in age, gender, and race/ethnicity, but had higher IL-6 levels. Mean LVmass for ACPA(+) vs ACPA(-) participants was 147g(39) and 146g(39), respectively; mean LVEF was 69%(7) and 70%(8), respectively. In adjusted analysis, LVmass and LVEF did not differ significantly between ACPA(+) and ACPA(-) participants. However, for every higher number of (+) ACPA, LVEF was 0.07% lower (p=0.02). Among individual ACPA, antibodies to Filaggrin 48-65 arg2v1cyc (p=0.04), histone 2B (p=0.01), and histone 2Bcit (p=0.02) were significantly associated with lower LVEF. No individual ACPA was associated with LVmass. Conclusion: In community-dwelling individuals without RA or heart failure, greater numbers of detectable ACPA were associated with lower LVEF, but not LVmass. Future studies are required to determine whether ACPA are associated with incident heart failure.

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged ≥65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n =192) or incident ESRD ( n =54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (±SD) was 78±5 years, mean eGFR was 63±18 ml/min per 1.73 m 2 , and median urine PIIINP was 2.6 (interquartile range, 1.4–4.2) μ g/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

Background Rheumatoid arthritis (RA) patients experience higher cardiovascular disease (CVD) risk and CVD-related mortality. MHC class II HLA-DRB1 alleles, or the shared epitope (SE), has also been linked to endothelial dysfunction in RA patients. It is not known whether this association exists in individuals who are RA-free, but who are at higher risk due to being a first-degree relative (FDR) of an RA patient. Objectives To determine the association between HLA-DRB1 alleles (*0401, *0404, *0405, *0408) and markers of endothelial injury in FDRs of RA patients, a population free of RA and RA-related medications. Methods From the Studies of the Etiology of RA, SERA, (a multicenter prospective study of preclinical RA, started in 2002), 113 FDRs who had been positive for any of 5 RA-related autoantibodies (Abs): rheumatoid factor (RF), RF isotypes – IgM, IgG, IgA, or anti-cyclic citrullinated peptide (anti-CCP2) on at least one of their visits, and 100 FDRs who had never been Ab positive were selected, frequency matched on age, sex, and field center site. No FDR met the 1987 ACR Criteria or 2010 EULAR/ACR Criteria for RA. In cross-sectional testing of single samples from baseline, the following were measured: endothelial injury markers: soluble intracellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin; and high resolution HLA-DRB1 typing for the*0401, *0404, *0405, and *0408 alleles using real-time polymerase chain reaction. ANCOVA was used to evaluate associations between HLA-DRB1 alleles, sVCAM, sICAM, and E-selectin, adjusting for age, sex, race, body mass index (BMI), Ab status, ever smoking, and current statin use. Results Among 213 FDRs, age was 50±18 yr, BMI was 27±6, 75% were women, 83% were Caucasian, 35% ever smoked, 11% were currently taking statins, and 38% were SE positive. sVCAM was significantly higher by 135ng/mL in FDRs with the HLA-DRB1*0404 allele (p=0.009) compared to FDRs without the *0404 allele (Table 1). E-selectin was higher by 23ng/mL in FDRs with the HLA-DRB1*0405 allele (p=0.03) compared to FDRs without the *0405 allele. Being positive for the SE was not significantly associated with sICAM, sVCAM, or E-selectin levels. Conclusions In RA-free FDRs, having an HLA-DRB1*0404 or HLA-DRB1*0405 allele was associated with markers of endothelial injury. Therefore, the genetic predisposition to RA could contribute to parallel development of atherosclerosis during the preclinical period of RA. References Gonzalez-Juanatey C et al., Am J Med 2003; 114:647–52. Gonzalez-Gay MA et al., Arth Rheum 2007; 57(1):125–132. Gersuk VH et al., J Immunol Methods. 2006 Dec 20; 317(1–2): 64–70. Disclosure of Interest None declared

Background: Hypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives. Methods: We evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications. Results: Average age was 51 and 69% were women. Mean SBP was 119 ± 18 and DBP was 74 ± 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for ≥1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 ± 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 ± 0.3 mm Hg (p = 0.04) higher. Anti-cit-fibrinogen A (211–230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit-clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7–8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first-degree relatives had 16.4± (p = 0.03) higher SBP and 12.1± mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives. Conclusion: In first-degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset.

Seropositive rheumatoid arthritis (RA) is characterized by abnormal elevations of circulating RA-related autoantibodies including antibodies to citrullinated protein antigens (ACPAs), which are highly specific for RA in the setting of inflammatory arthritis1,2. Multiple studies have also demonstrated that these ACPA elevations are present years prior to arthritis onset in RA, and in case-control studies, ACPAs are highly specific for the future development of arthritis that is classifiable as RA3–5. Therefore, there is hope that ACPA testing can be used to identify currently asymptomatic individuals with elevated risk for the future development of clinically-apparent RA who can be studied to understand the natural history of RA as well as be utilized to develop predictive and preventive approaches for disease6. However, there are several limitations to applying ACPA testing to identify individuals who are at elevated risk for clinically-apparent RA which include: 1) there are multiple commercial ACPA assays that differ in antigen and autoantibody isotype reactivities, 2) there are limited data comparing the accuracy of each of these assays in established RA, and 3) there are limited data comparing the ability of individual ACPA assays to predict future clinically-apparent RA in currently asymptomatic individuals1. In addition, ACPA positivity is incorporated in the 2010 American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) classification criteria for RA, yet there is not an established gold standard CCP assay - an issue that could have a clinically meaningful impact on classification and diagnosis of inflammatory arthritis if ACPA assays differ significantly in performance. As such, to better understand the significance of elevated ACPA levels in individuals with and without a current classification of RA, we evaluated commonly utilized commercially-available ACPA assays that test for autoantibodies to cyclic citrullinated peptides (anti-CCP) in subjects with established RA, subjects at elevated risk for development of classifiable RA, and controls.

Objective To examine reactivity to anti–citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)–related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. Methods Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti–cyclic citrullinated peptide 2 [anti–CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for ≥9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for ≥9 ACPAs) and RA-related characteristics were examined. Results Fifty-seven percent of anti–CCP-2–positive first-degree relatives and 8% of anti–CCP-2– negative first-degree relatives were positive for ≥9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of ≥1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04–1.34), with the greatest risk of having ≥1 tender joint seen in first-degree relatives positive for ≥9 ACPAs (OR 5.00, 95% CI 1.37–18.18). Conclusion RA-free first-degree relatives (even those negative for RF and anti–CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted.

Adipose tissue has been recognized as an endocrine organ. Cytokines released from adipose tissue not only influence lipid metabolism, they also affect multiple organ systems such as the immune and nervous systems, and of interest in this review, the cardiovascular system. While there are multiple depots of adipose tissue, visceral adipose tissue appears to be the most metabolically active. This fat depot has been linked to dysfunction of the vascular endothelium with the subsequent development of atherosclerosis and incident cardiovascular events. In this regard and within the last two years, several studies have examined the effect of visceral adipose tissue on subclinical and clinical CVD outcomes. This review highlights these findings and focuses on the associations between visceral adipose tissue and ethnicity, risk factors, vascular changes, clinical effects and cardiovascular disease outcomes.

Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD.

Author(s): Woodell, Tyler B; Hughes-Austin, Jan M; Tran, Tiffany V; Malhotra, Atul; Abdelmalek, Joseph A; Rifkin, Dena E | Abstract: ObjectivesThe objective of this study was to determine the relationship between chronic kidney disease [CKD; measured using cystatin C-based estimated glomerular filtration rate (eGFR)] and abnormal ambulatory blood pressure (including nocturnal dipping) in healthy older adults. Further, this study aimed to assess the agreement between clinic and ambulatory blood pressure monitoring.MethodsSerum cystatin C levels were measured to calculate eGFR. Participants underwent clinic and 24-h ambulatory blood pressure measurements. Multiple linear regression was performed to examine the association between reduced cystatin C-based eGFR (CKDcys) and blood pressure parameters. Bland-Altman analysis was carried out to evaluate the agreement between clinic and ambulatory measurements.ResultsThe average age was 72 years. There were 60 individuals with CKDcys (eGFRl60 ml/min/1.73 m). Compared with those without CKDcys, individuals with CKDcys were older, more likely to have hypertension, and less likely to have normal dipping patterns. On multivariate analysis, the presence of CKDcys was found to be significantly associated with a lower mean ambulatory diastolic blood pressure (-2 mmHg, P=0.048), but not with nocturnal dipping or other blood pressure parameters. Clinic systolic blood pressure (SBP) significantly overestimated the mean wake-time ambulatory SBP; the mean difference was 11 mmHg for those without CKDcys (95% limits of agreement -14 to 35 mmHg) and 14 mmHg for those with CKDcys (95% limits of agreement -13 to 41 mmHg); there was no statistically significant effect modification by CKD status.ConclusionIn older, seemingly healthy adults, mild CKD was associated with lower ambulatory diastolic blood pressure. The presence of CKD did not affect interpretation of clinic versus ambulatory blood pressure monitoring, although the accuracy of clinic SBP was poor.

Background: CVD is accelerated in RA, and risk of CVD death is 50% higher in RA patients. Physical activity (PA) mitigates increased CVD risk, but RA patients typically have less PA. It is not known whether PA declines prior to RA onset, or whether joint symptoms (sxs) contribute to PA decline. We sought to determine whether RA-related joint sxs were associated with PA over time in first-degree relatives (FDRs) of RA patients, a population at increased risk for future RA. Methods: In the Studies of the Etiology of RA (SERA), we evaluated associations between presence of joint sxs and hours of PA in 878 FDRs; of whom, 376 had ≥2 visits. A physician confirmed joint swelling; participants self-reported stiffness and pain in the wrist, elbow, or any MCP, PIP, or MTP joints. Hours sleeping, sitting, and performing slight, moderate, or heavy activity during a typical 24-hour day were obtained through questionnaire, weighted to reflect metabolic expenditure, and calculated as follows: PA = (1.0*h sleep + 1.1*h sedentary + 1.5*h slight + 2.4*h moderate + 5.0*h heavy ). Linear mixed models were used to evaluate associations between joint sxs and change in PA over time, adjusting for age, sex, race, BMI, smoking, and positivity for RA-related autoantibodies Results: Mean baseline age was 50±16 years. 74% were female, 78% were White, 7% had joint swelling, 15% had joint stiffness, and 24% had joint pain. Average PA was 37±7. At baseline, PA was higher in FDRs with joint stiffness (B=1.27±0.64, p=0.05) and joint pain (B=1.43±0.54, p=0.01), and lower in FDRs with joint swelling (B=-1.50±0.91, p=0.10). Adjusting for baseline PA, baseline joint swelling, stiffness, and pain were not significantly associated with changes in PA. However, change in joint swelling was associated with increased PA; and changes in joint stiffness and pain were associated with decreased PA. (Table) Conclusion: Joint sxs may not predict future PA, but PA may be lower at the time joint sxs occur. Clinicians should address joint sxs as part of their PA intervention in CVD prevention.

ObjectivesThe aim of this study was to determine the correlation between coronary artery calcium (CAC) scores on 3mm electrocardiography (ECG)-gated computed tomography (CT) scans and standard 6 mm chest CT scans, and to compare relative strength of associations of CAC on each scan type with mortality risk.BackgroundCoronary artery calcification predicts cardiovascular disease (CVD) and all-cause mortality, and istypically measured on ECG-gated 3 mm CT scans. Patients undergo standard 6 mm chest CTs for various clinical indications much more frequently, but CAC is not usually quantified. To better understand the usefulness of standardchest CTs to quantify CAC, we conducted a case-control study among persons who had both scan types.MethodsBetween 2000 and 2003, 4,544 community-living individuals self- or physician-referred for "whole-body" CT scans, had 3 mm ECG-gated CTs and standard 6 mm chest CTs, and were followed for mortality through 2009. In this nested case-control study, we identified 157 deaths and 494 controls frequency matched (1:3) on age and sex. The Agatston method quantified CAC on both scan types. Unconditional logistic regression determined associations with mortality, accounting for CVD risk factors.ResultsParticipants were 68 ± 11 years of age and 63% male. The Spearman correlation of CAC scores between the 2scan types was 0.93 (p< 0.001); median CAC scores were lower on 6 mm CTs compared to 3 mm CTs (22vs.104 Agatston units, p< 0.001). Adjusted for traditional CVD risk factors, each standard deviation higher CACscore on 6 mm CTs was associated with 50% higher odds of death (odds ratio: 1.5; 95% confidence interval: 1.2to 1.9), similar to 50% higher odds on the 3 mm ECG-gated CTs (odds ratio: 1.5; 95% confidence interval: 1.1to1.9).ConclusionsCAC scores on standard 6 mm chest CTs are strongly correlated with 3 mm ECG-gated CTs and similarly predict mortality in community-living individuals. Chest CTs performed for other clinical indications may provide anuntapped resource to garner CVD risk information without additional radiation exposure or expense.

ObjectiveWe investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development.MethodsWe studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression.ResultsAdjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort.ConclusionsIn first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.

Author(s): Hughes-Austin, Jan M; Deane, Kevin D; Giles, Jon T; Derber, Lezlie A; Zerbe, Gary O; Dabelea, Dana M; Sokolove, Jeremy; Robinson, William H; Holers, V Michael; Norris, Jill M | Abstract: BACKGROUND:Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations. METHODS:We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the 'high risk autoantibody profile (HRP)' as it has been shown in prior work to be g96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications. RESULTS:In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations. CONCLUSIONS:Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA.

Background: High serum potassium (K) is associated with death in chronic kidney disease (CKD) patients, and in acute illness. Associations in other settings are uncertain. We determined associations between K concentrations and total mortality, coronary heart disease (CHD) death, and sudden cardiac death (SCD) in an older, community-dwelling population. Methods: Among 5137 CHS participants aged ≥ 65 years at baseline, we evaluated associations between serum K categories [< 4.0, 4.0-4.5, 4.5-5.0, & ≥ 5.0 mMol/dL] with CHD death, SCD, and all-cause mortality using Cox proportional hazards models. We also evaluated whether associations differed by angiotensin converting enzyme (ACE) inhibitor / angiotensin II receptor blocker (ARB) use, diuretic use, and CKD status [eGFR < 60 vs. higher]. All CHD and SCD events were adjudicated by committee. Results: Mean age was 72 years, 39% were male, and 17% were Black. Individuals in the ≥ 5.0 mMol/dL category were older, more frequently men, diabetic, to have CKD, and to use ACE/ARBs. They were also less likely to use diuretics. Mean follow-up was 14 ± 6 years during which there were 4122 total deaths including 971 CHD deaths. Follow-up for SCD was 12 ± 5 years during which there were 162 SCD events. In models adjusted for demographics, CVD risk factors, eGFR, and use of ACE/ARBs, diuretics and K supplements, those with K ≥ 5.0 mMol/dL had 32% higher risk of all-cause mortality (HR 1.32; 95% CI: 1.07-1.63) than the 4.0-4.5mMol/dL reference category. The association was similar irrespective of diuretic or ACE/ARB use or by CKD status (p interaction all > 0.18). Those with K < 4.0 mMol/dL had 14% higher risk of all-cause mortality (HR 1.14; 95% CI: 1.05-1.23) than the reference category; and this association was limited to those with K < 4.0 mMol/dL and were not on diuretics and did not have CKD (p interaction both < 0.02). No association of K < 4.0 mMol/dL with mortality was observed in those on diuretics or with CKD. There was no significant association of either high or low K with either CHD death (HR 1.08; 95% CI: 0.71-1.65; and HR 0.96; 95% CI: 0.81-1.13, respectively) or SCD (HR 1.13; 95% CI: 0.41-3.11; and HR 1.01; 95% CI: 0.68-1.50, respectively) in adjusted models. Conclusions: Higher and lower serum K are independently associated with all-cause mortality but not CHD death or SCD in older community-dwelling individuals. Mechanisms linking high and low K with mortality from diseases other than CHD and SCD require future study.

ObjectiveHigher serum leptin levels have been associated with a modestly higher incidence of cardiovascular disease in studies involving mostly Caucasian men. We aimed to assess the hypothesis that higher baseline levels of serum leptin are associated with higher risk of future cardiovascular disease in a diverse cohort.MethodsThe Multi-Ethnic Study of Atherosclerosis (MESA) is a modern, community-based, ethnically-diverse, and sex-balanced prospective cohort study of US adults free from cardiovascular disease. Serum leptin was measured in an ancillary study in 2002-2005. This analysis included 1905 MESA participants with baseline leptin and incident cardiovascular event data. Leptin levels were modeled as a log-transformed continuous variable and multivariable-adjusted Cox regression was performed for the primary outcome of hard cardiovascular disease, including coronary heart disease and stroke.ResultsThe median follow-up was 7.6 years (25th-75th 7.1-8.3) with 7051 and 6738 person-years of follow-up in women and men. A hard cardiovascular disease event occurred in 47 women and 63 men. The age- and ethnicity-adjusted hazard ratio estimates for a 1 standard deviation increase in ln(leptin) were 1.16 in women (95% CI 0.78-1.73, p=0.46) and 0.91 (95% CI 0.69-1.20, p=0.51) in men. Pooling sexes, and adjusting for sex in addition to age and ethnicity, estimates were 0.98 (95% CI 0.78-1.23, p=0.89). With additional adjustment for cardiovascular risk factors, the results remained nonsignificant: 0.87 (95% CI 0.68-1.11, p=0.26).ConclusionIn conclusion, in a modern, US prospective cohort study of multi-ethnic women and men of multi-ethnic backgrounds, leptin levels are not associated with incident cardiovascular events.

Hispanic Americans (HA) are a significant and increasing segment of the population who must be considered in future health planning. HA, compared to European Americans (EA), have a lower prevalence of coronary artery disease, but higher burden of cardiovascular disease risk factors. It remains unclear if this observation termed the 'Hispanic Paradox' also exists for vascular beds outside the heart. We present a review of the literature which suggests that this paradox may also exist for arteries in the extremities and neck.

Adipokines regulate metabolic processes linked to coronary artery (CAC) and abdominal aorta calcification (AAC). Because adipokine and other adiposity-associated inflammatory marker (AAIM) secretions differ between visceral and subcutaneous adipose tissue, we hypothesized that central adiposity modifies associations between AAIMs and CAC and AAC. We evaluated 1878 MESA participants with complete measures of AAIMs, anthropometry, CAC, and AAC. Associations of AAIMs with CAC and AAC prevalence and severity were analyzed per standard deviation of predictors (SD) using log binomial and linear regression models. The waist-to-hip ratio (WHR) was dichotomized at median WHR values based on sex/ethnicity. CAC and AAC prevalence were defined as any calcium (Agatston score >0). Severity was defined as ln (Agatston score). Analyses examined interactions with WHR and were adjusted for traditional cardiovascular disease risk factors. Each SD higher interleukin-6 (IL-6), fibrinogen and CRP was associated with 5% higher CAC prevalence; and each SD higher IL-6 and fibrinogen was associated with 4% higher AAC prevalence. Associations of IL-6 and fibrinogen with CAC severity, but not CAC prevalence, were significantly different among WHR strata. Median-and-above WHR: each SD higher IL-6 was associated with 24.8% higher CAC severity. Below-median WHR: no association ( pinteraction=0.012). Median-and-above WHR: each SD higher fibrinogen was associated with 19.6% higher CAC severity. Below-median WHR: no association ( pinteraction=0.034). Adiponectin, leptin, resistin, and tumor necrosis factor-alpha were not associated with CAC or AAC prevalence or severity. These results support findings that adiposity-associated inflammation is associated with arterial calcification, and further add that central adiposity may modify this association.

Background: Classic CVD risk factors associated with isolated small vessel peripheral artery disease (iSV-PAD) include older age, male sex, longer smoking duration, and higher LDL cholesterol levels. These CVD risk factors have been linked to atherosclerosis in several vascular beds and to cardiac ischemia. It is not known whether iSV-PAD shares these same links, especially in community-dwelling older adults. Thus, in the Rancho Bernardo (RB) Study, we investigated whether iSV-PAD was associated with measures of atherosclerosis and cardiac ischemia. Methods: Among 965 RB Study participants with complete measures of ankle-brachial index (ABI), toe-brachial index (TBI), and measures of cardiac ischemia [self-reported angina, major Q wave on electrocardiogram (ECG), and any ECG abnormality], we evaluated associations between cardiac ischemia and iSV-PAD. In a subset of 387 RB participants free of diagnosed CVD, we evaluated associations between measures of atherosclerosis [coronary artery calcium (CAC) (Agatston scores and calcium volume) and internal carotid intima-media thickness (cIMT)] with iSV-PAD. Isolated SV-PAD was defined by bilateral normal ABI (1.0-1.4) with bilateral TBI < 0.7. Associations of measures of atherosclerosis and cardiac ischemia with iSV-PAD were evaluated using logistic regression in staged models, adjusted for age, sex, anthropometrics, lifestyle, comorbidities, and medications. Results: More likely to have iSV-PAD were participants who ever had angina (OR=2.1, 95% CI: 1.04-4.2) or had major Q wave on ECG (OR=4.2, 95% CI: 1.1-15.5). There were too few to stratify by sex. No statistically significant associations were observed for measures of atherosclerosis with iSV-PAD. (Figure 1) Conclusion: Strong associations of cardiac ischemia, coupled with null associations of atherosclerosis, with iSV-PAD suggest that iSV-PAD may indicate vascular pathology different from atherosclerosis. Further investigation of endothelial dysfunction and iSV-PAD may elucidate underlying pathology.

Author(s): Smagula, Stephen F; Reynolds, Charles F; Ancoli-Israel, Sonia; Barrett-Connor, Elizabeth; Dam, Thuy-Tien; Hughes-Austin, Jan M; Paudel, Misti; Redline, Susan; Stone, Katie L; Cauley, Jane A; Osteoporotic Fractures in Men (MrOS) Research Group | Abstract: ObjectivesTo investigate the association of mood and anxiety symptoms with sleep architecture (the distribution of sleep stages) in community-dwelling older men.MethodWe used in-home unattended polysomnography to measure sleep architecture in older men. Men were categorized into 4 mental health categories: (a) significant depressive symptoms only (DEP+ only, Geriatric Depression Scale ≥ 6), (b) significant anxiety symptoms only (ANX+ only, Goldberg Anxiety Scale ≥ 5), (c) significant depressive and anxiety symptoms (DEP+/ANX+), or (d) no significant depressive or anxiety symptoms (DEP-/ANX-).ResultsCompared with men without clinically significant symptomology, men with depressive symptoms spent a higher percentage of time in Stage 2 sleep (65.42% DEP+ only vs 62.47% DEP-/ANX-, p = .003) and a lower percentage of time in rapid eye movement sleep (17.05% DEP+ only vs 19.44% DEP-/ANX-, p = .0005). These differences persisted after adjustment for demographic/lifestyle characteristics, medical conditions, medications, and sleep disturbances, and after excluding participants using psychotropic medications. The sleep architecture of ANX+ or DEP+/ANX+ men did not differ from asymptomatic men.DiscussionDepressed mood in older adults may be associated with accelerated age-related changes in sleep architecture. Longitudinal community-based studies using diagnostic measures are needed to further clarify relationships among common mental disorders, aging, and sleep.

To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA.Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283).In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels ≥3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (κ = 0.76) but poor in FDRs without inflammatory arthritis (κ = 0.25).Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation.