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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 - Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial.
METHODS - Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate.
RESULTS - The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up.
CONCLUSIONS - Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.
© 2016 S. Karger AG, Basel.
In regions of the circulation where vessels are straight and unbranched, blood flow is laminar and unidirectional. In contrast, at sites of curvature, branch points, and regions distal to stenoses, blood flow becomes disturbed. Atherosclerosis preferentially develops in these regions of disturbed blood flow. Current therapies for atherosclerosis are systemic and may not sufficiently target these atheroprone regions. In this study, we sought to leverage the alterations on the luminal surface of endothelial cells caused by this atheroprone flow for nanocarrier targeting. In vivo phage display was used to discover unique peptides that selectively bind to atheroprone regions in the mouse partial carotid artery ligation model. The peptide GSPREYTSYMPH (PREY) was found to bind 4.5-fold more avidly to the region of disturbed flow and was used to form targeted liposomes. When administered intravenously, PREY-targeted liposomes preferentially accumulated in endothelial cells in the partially occluded carotid artery and other areas of disturbed flow. Proteomic analysis and immunoblotting indicated that fibronectin and Filamin-A were preferentially bound by PREY nanocarriers in vessels with disturbed flow. In additional experiments, PREY nanocarriers were used therapeutically to deliver the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), which we have previously shown to be deficient in regions of disturbed flow. This intervention increased vascular BH4 and reduced vascular superoxide in the partially ligated artery in wild-type mice and reduced plaque burden in the partially ligated left carotid artery of fat fed atheroprone mice (ApoE(-/-)). Targeting atheroprone sites of the circulation with functionalized nanocarriers provides a promising approach for prevention of early atherosclerotic lesion formation.
PURPOSE - Neonates placed on veno-arterial extracorporeal membrane oxygenation (VA-ECMO) undergo either carotid repair or ligation at decannulation. Study aims were to evaluate carotid patency rates after repair and to compare early neurologic outcomes between repaired and ligated patients.
METHODS - A retrospective study of all neonates without congenital heart disease (CHD) who had VA-ECMO between 1989 and 2012 was completed using our institutional ECMO Registry. Carotid patency after repair, neuroimaging studies, and auditory brainstem response (ABR) testing at time of discharge were examined.
RESULTS - 140 neonates were placed on VA-ECMO during the study period. Among survivors, 84% of carotids repaired and imaged remained patent at last study. No significant differences were observed between infants in the repaired and ligated groups regarding diagnosis, ECMO duration, or length of stay. A large proportion (43%) developed a severe brain lesion after VA-ECMO, but few failed their ABR testing. Differences in early neurologic outcomes between the two groups of survivors were not significant.
CONCLUSIONS - At this single institution, carotid patency is excellent following repair at ECMO decannulation. No increased incidence of severe brain lesions or greater neurosensory impairment in the repair group was observed. Further studies are needed to investigate the effects of ligation on longer-term neurocognitive outcomes.
Copyright © 2015 Elsevier Inc. All rights reserved.
Activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and reactive oxygen species (ROS) promote neointimal hyperplasia after vascular injury. CaMKII can be directly activated by ROS through oxidation. In this study, we determined whether abolishing the oxidative activation site of CaMKII alters vascular smooth muscle cell (VCMC) proliferation, migration and apoptosis in vitro and neointimal formation in vivo. VSMC isolated from a knock-in mouse with oxidation-resistant CaMKIIδ (CaMKII M2V) displayed similar proliferation but decreased migration and apoptosis. Surprisingly, ROS production and expression of the NADPH oxidase subunits p47 and p22 were decreased in M2V VSMC, whereas superoxide dismutase 2 protein expression was upregulated. In vivo, after carotid artery ligation, no differences in neointimal size or remodeling were observed. In contrast to VSMC, CaMKII expression and autonomous activity were significantly higher in M2V compared to WT carotid arteries, suggesting that an autoregulatory mechanism determines CaMKII activity in vivo. Our findings demonstrate that preventing oxidative activation of CaMKII decreases migration and apoptosis in vitro and suggest that CaMKII regulates ROS production. Our study presents novel evidence that CaMKII expression in vivo is regulated by a negative feedback loop following oxidative activation.
Published by Elsevier Inc.
PURPOSE - Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, we sought to determine how well lipids measured at baseline and at 20 years predict the presence of subclinical atherosclerosis.
METHODS - Complete risk factor, coronary artery calcification (CAC), and carotid intima media thickness (CIMT) data were available for 2435 participants. Lipids were categorized into quartiles, CAC at Y20 was dichotomized as present/absent, and CIMT was dichotomized as ≥84 or <84th overall percentile. Multivariable logistic regression was used to model the association between lipids and CAC/CIMT. C statistics were used to assess the discriminative value of each lipid measure in predicting the presence of CAC or CIMT at Y20.
RESULTS - Lipid levels measured in young adulthood as well as middle age were both associated with subclinical disease in middle age. The discriminatory value of lipids was virtually identical at baseline, when participants were 18-30 years of age, and 20 years later. Neither baseline nor Y20 lipid data were strong predictors of Y20 subclinical disease despite statistically significant associations.
CONCLUSIONS - These results are consistent with a growing body of evidence that early-life exposure to nonoptimal lipids matters and lifestyle modifications administered earlier in the lifespan could slow the progress of the atherosclerotic plaques.
Copyright © 2013 Elsevier Inc. All rights reserved.
Carotid intima-media-thickness (cIMT) and carotid distensibility (distensibility), structural and functional properties of carotid arteries respectively, are early markers, as well as strong predictors of cardiovascular disease (CVD). The characteristic of these two parameters in individuals with BMI>40.0 kg/m(2) (Class III obesity), however, are largely unknown. The present study was designed to document cIMT and distensibility in this population and to relate these to other factors with established association with CVD in obesity. The study included 96 subjects (65 with BMI>40.0 kg/m(2) and 31, age- and gender-matched, with BMI of 18.5 to 30.0 kg/m(2)). cIMT and distensibility were measured by non-invasive high resolution ultrasonography, circulatory CD133(+)/KDR(+) angiogenic cells and endothelial microparticles (EMP) by flow cytometry, and plasma levels of adipokines, growth factors and cytokines by Luminex immunoassay kits. The study results demonstrated increased cIMT (0.62±0.11 mm vs. 0.54±0.08 mm, P = 0.0002) and reduced distensibility (22.52±10.79 10(-3)kpa(-1)vs. 29.91±12.37 10(-3)kpa(-1), P<0.05) in individuals with BMI>40.0 kg/m(2). Both cIMT and distensibility were significantly associated with traditional CVD risk factors, adiposity/adipokines and inflammatory markers but had no association with circulating angiogenic cells. We also demonstrated, for the first time, elevated plasma EMP levels in individuals with BMI>40.0 kg/m(2). In conclusion, cIMT is increased and distensibility reduced in Class III obesity with the changes predominantly related to conventional CVD risk factors present in this condition, demonstrating that both cIMT and distensibility remain as CVD markers in Class III obesity.
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.
In this work, a new approach for tubular structure segmentation is presented. This approach consists of two parts: (1) automatic model construction from manually segmented exemplars and (2) segmentation of structures in unknown images using these models. The segmentation problem is solved by finding an optimal path in a high-dimensional graph. The graph is designed with novel structures that permit the incorporation of prior information from the model into the optimization process and account for several weaknesses of traditional graph-based approaches. The generality of the approach is demonstrated by testing it on four challenging segmentation tasks: the optic pathways, the facial nerve, the chorda tympani, and the carotid artery. In all four cases, excellent agreement between automatic and manual segmentations is achieved.