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BACKGROUND - Disturbances in vitamin D metabolism are common in patients with end-stage renal disease and may contribute to vascular dysfunction.
STUDY DESIGN - Cross-sectional.
SETTING & PARTICIPANTS - We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery.
FACTOR - 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery.
OUTCOMES - Vasodilator functions and measurements of arterial stiffness.
MEASUREMENTS - Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use.
RESULTS - Mean participant age was 55±13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses.
LIMITATIONS - Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease.
CONCLUSIONS - Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting.
Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.

BACKGROUND - Androgen deprivation therapy (ADT) is a standard treatment for patients with aggressive prostate cancer. Although ADT improves survival, it increases the risk of diabetes. Emerging evidence suggests that ADT increases adverse cardiovascular events as early as 3 months after initiation in patients with cardiovascular disease, but the mechanism is unknown. We hypothesized that ADT may impair endothelium-dependent vasodilation due to increases in lipids and insulin resistance and may provide a link for heightened cardiovascular risk in this population.
METHODS AND RESULTS - We prospectively evaluated conduit artery endothelium-dependent and -independent vasodilation, lipids, and insulin resistance in 16 consecutively treated men (mean age 66 ± 7 years; 25% with diabetes) with prostate cancer before and after 3 months of ADT. High-resolution B-mode ultrasound was used to assess flow-mediated (endothelium-dependent) and nitroglycerine-mediated (endothelium-independent) brachial artery vasodilation. ADT significantly increased insulin resistance, total cholesterol, HDL, and LDL. Endothelium-dependent vasodilation was greater at 3 months than at baseline (10.8% [interquartile range: 7.7% to 14.6%] versus 8.9% [interquartile range: 4.0% to 12.6%], respectively; P=0.046, allometric P=0.037). Nitroglycerine-mediated vasodilation did not change from baseline (P>0.2). The subset of participants on ADT for 6 months returned for reevaluation at 1 year. In this group, endothelium-dependent vasodilation increased from baseline to 3 months and returned to baseline 6 months after ADT withdrawal (9.4% [interquartile range: 6.9% to 10.9%], 11.6% [interquartile range: 7.9% to 15.2%], and 9.0% [interquartile range: 5.1% to 12.5%], respectively; P=0.05).
CONCLUSIONS - In contrast to our expectation, ADT improved endothelium-dependent vasodilation and its cessation returned endothelium-dependent vasodilation to baseline. Determining the mechanism of this change requires further investigation.
© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

OBJECTIVE - It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD.
APPROACH AND RESULTS - Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8-126.7] versus 10.6 [6.1-38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6-38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.
CONCLUSIONS - Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification.
© 2014 American Heart Association, Inc.

BACKGROUND - D-Dimer elevations have been associated with a striking increase in mortality in HIV-infected patients. However, D-Dimer has not been directly linked to endothelial dysfunction in HIV.
METHODS - In this cross-sectional study, we used flow-mediated dilation (FMD) of the brachial artery to measure endothelial function and several biomarkers to measure systemic inflammation and coagulation activation in HIV-infected adults on stable antiretroviral therapy with HIV-1 RNA levels <400 copies/ml. Multivariable linear regression was used to model FMD by these markers, traditional cardiovascular risk factors and HIV-related characteristics.
RESULTS - Analysis included 98 subjects (88% male, median age 47.5 years, CD4(+) T-cells 578.5 cells/mm(3)); all on ART (52% on protease inhibitors). The only factors independently associated with FMD were D-Dimer and body mass index.
CONCLUSIONS - We show for the first time an independent association between D-Dimer and endothelial dysfunction in virologically suppressed, HIV-infected adults on stable antiretroviral therapy, potentially explaining the link between D-Dimer and mortality in HIV.

OBJECTIVE - Several bone marrow-derived cell populations have been identified that may possess angiogenic activity and contribute to vascular homeostasis in experimental studies. We examined the extent to which lower quantities of these circulating angiogenic cell phenotypes may be related to impaired vascular function and greater arterial stiffness.
METHODS - We studied 1948 Framingham Heart Study participants (mean age, 66±9 years; 54% women) who were phenotyped for circulating angiogenic cells: CD34+, CD34+/KDR+, and early outgrowth colony forming units (CFU). Participants underwent non-invasive assessments of vascular function including peripheral arterial tone (PAT), arterial tonometry, and brachial reactivity testing.
RESULTS - In unadjusted analyses, higher CD34+ and CD34+/KDR+ concentrations were modestly associated with lower PAT ratio (β=-0.052±0.011, P<0.001 and β=-0.030±0.011, P=0.008, respectively) and with higher carotid-brachial pulse wave velocity (β=0.144±0.043, P=0.001 and β=0.112±0.043, P=0.009), but not with flow-mediated dilation; higher CD34+ was also associated with lower carotid-femoral pulse wave velocity (β=-0.229±0.094, P=0.015). However, only the association of lower CD34+ concentration with higher PAT ratio persisted in multivariable analyses that adjusted for standard cardiovascular risk factors. In all analyses, CFU was not associated with measures of vascular function or arterial stiffness.
CONCLUSIONS - In our large, community-based sample of men and women, circulating angiogenic cell phenotypes largely were not associated with measures of vascular function or arterial stiffness in analyses adjusting for traditional risk factors.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The brachial artery is rarely injured after closed dislocation of the elbow. We describe an unusual variation of this injury, namely, a delayed thrombosis of the brachial artery after a closed dislocation sustained during a low-energy fall. This has not previously been described in the English literature, but may be more common than this suggests. We stress the importance of a thorough neurovascular examination and vigilance in regard to this potentially disastrous complication.

OBJECTIVE - Arterial stiffness, assessed by the augmentation index and pulse wave velocity, is an independent risk factor for cardiovascular disease. Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis and increased cardiovascular mortality. We examined the hypothesis that augmentation index and pulse wave velocity are increased in RA, and are related to coronary artery atherosclerosis.
METHODS - We measured augmentation index and brachial pulse wave velocity in 117 patients with RA [57 with early (< 6 yrs) and 60 with late disease (> 10 yrs)] and 65 healthy controls. Coronary artery calcification was measured by electron beam computed tomography. Augmentation index and pulse wave velocity were compared in patients with early RA, late RA, and controls, and the association with coronary atherosclerosis was examined.
RESULTS - Patients with late RA had a higher augmentation index (median 33.8%, interquartile range 27.5% 37.0%) than those with early disease (median 27.5%, IQR 21.0% 34.0%) (p = 0.008) and controls (median 27.0%, IQR 20.4% 33.0%) (p < 0.001). After adjusting for height and cardiovascular risk factors, the association between late disease and augmentation index remained significant (p = 0.02). Augmentation index was associated with coronary calcification score (rs = 0.19, p = 0.046), and the association was marginal after adjustment for cardiovascular risk factors, disease status, and disease activity (p = 0.09). There was no significant difference in brachial pulse wave velocity among patients with late (9.2 +/- 1.7 m/s) and early RA (9.1 +/- 1.6 m/s) and controls (8.9 +/- 1.5 m/s) (p = 0.78).
CONCLUSION - Patients with RA have increased augmentation index independent of cardiovascular risk factors. Augmentation index was associated with coronary artery calcification in patients with RA; this was attenuated after adjusting for cardiovascular risk factors.

BACKGROUND - Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study.
METHODS - We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency > or =0.10, genotype call rate > or =0.80, and Hardy-Weinberg equilibrium p > or = 0.001.
RESULTS - We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. We confirmed modest-to-strong heritabilities (estimates 0.30-0.52) for several Echo, ETT and BA function traits. Overall, p < 10(-5) in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (SLIT2, p = 1.17*10(-7)); LV systolic dimension, rs10504543 (KCNB2, p = 5.18*10(-6)); LV mass, rs10498091 (p = 5.68*10(-6)); Left atrial size, rs1935881 (FAM5C, p = 6.56*10(-6)); exercise heart rate, rs6847149 (NOLA1, p = 2.74*10(-6)); exercise systolic blood pressure, rs2553268 (WRN, p = 6.3*10(-6)); BA baseline flow, rs3814219 (OBFC1, 9.48*10(-7)), and FMD, rs4148686 (CFTR, p = 1.13*10(-5)). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; chromosome 5); the 1.5 LOD support interval included NRG2.
CONCLUSION - In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.

OBJECTIVES - Endothelial dysfunction is frequently present in patients with systemic lupus erythematosus and may increase their risk of premature coronary artery disease. In this pilot study we have characterized the relationship between endothelial function, measures of disease activity, and cardiovascular risk factors in patients with lupus.
METHODS - Clinical characteristics and cardiovascular risk factors were evaluated in 20 patients with lupus. Flow-mediated dilation of the brachial artery was measured using high resolution ultrasound and the presence or absence of coronary calcification determined by electron-beam computed tomography. The relationship between these variables and flow-mediated dilation was determined using Spearman correlation coefficients (RHO) and Mann Whitney-Wilcoxon tests.
RESULTS - Twenty patients (17 female) median age (interquartile range) 42.5 (32.0-47.5) years were studied. The median flow-mediated vasodilation was 3.6% (1.7%-7.7%). In patients with coronary calcification (n = 6), flow-mediated dilation was 2.1% (-0.42%-3.6%) compared with 4.0% (3.5%-8.3%) in those without (p = 0.12). There was no significant relationship between flow-mediated dilation and markers of disease activity, duration of disease, and cardiovascular risk factors. Lower flow-mediated dilation was associated with duration of corticosteroid therapy (RHO = -0.44, p = 0.05).
CONCLUSIONS - In these preliminary results, endothelial dysfunction is associated with long-term exposure to corticosteroids.

BACKGROUND - Endothelial dysfunction is a critical intermediate phenotype in the pathogenesis of cardiovascular disease. We evaluated the relative contributions of distinct biological pathways to interindividual variation in endothelial function by relating prototype biomarkers (representing these pathways) to brachial artery vasodilator function.
METHODS AND RESULTS - We investigated the cross-sectional relations of a panel of 7 biomarkers measured at a routine examination to brachial artery vasodilator function (flow-mediated dilation [FMD] and reactive hyperemia) assessed at a subsequent examination (mean interval, 2.9 years) in 2113 Framingham Heart Study participants (mean age, 61 years; 54% women). We selected biomarkers from 4 biological domains: neurohormonal (N-terminal pro-atrial natriuretic peptide [N-ANP], B-type natriuretic peptide [BNP], renin, aldosterone), hemostatic factors (plasminogen activator inhibitor-1 [PAI-1]), inflammation (C-reactive protein [CRP]), and target organ damage (urine albumin-creatinine ratio). In age- and sex-adjusted models, several biomarkers were related to baseline brachial artery diameter (PAI-1, CRP, urine albumin-creatinine ratio), baseline mean flow (N-ANP, BNP, PAI-1, CRP, aldosterone), FMD (N-ANP, PAI-1, CRP, renin), and reactive hyperemia (BNP, PAI-1, CRP, renin, urine albumin-creatinine ratio). In multivariable analyses relating the 7 biomarkers conjointly to each vascular function measure (adjusting for known risk factors), N-ANP and renin were positively related to FMD (P=0.001 and P=0.04, respectively), and N-ANP was inversely related to baseline mean flow velocity (P=0.01). None of the other biomarkers was significantly related to the vascular function measures studied.
CONCLUSIONS - In our large community-based sample, a conservative strategy relating several biomarkers to vascular endothelial function identified plasma N-ANP as a key correlate of mean flow under basal conditions and of FMD in response to forearm cuff occlusion.