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Background: Evidence suggests that the renin-angiotensin-aldosterone system (RAAS) interacts with the vitamin D-fibroblast growth factor 23-Klotho axis. We investigated whether circulating mineral metabolism markers modify outcomes in response to RAAS inhibition in subjects with advanced chronic kidney disease (CKD). Methods: In this retrospective cohort study, we analyzed the association of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use with all-cause mortality and dialysis initiation among 1,753 subjects (1,099 CKD, estimated glomerular filtration rate 18 ± 6 ml/min/1.73 m2 and 654 end-stage renal disease [ESRD]) from the Homocysteine in Kidney and End Stage Renal Disease (HOST) study. A propensity score analysis accounted for indication bias and Cox regression models adjusted for mineral metabolism markers. Results: Mean follow-up was 3.2 years; 714 (41%) subjects died and 615 (56%) initiated dialysis. In adjusted analyses, all subjects treated with ACEI/ARB had a significantly lower hazard of death (hazards ratio (HR) 0.81, 95% CI 0.70-0.95, p = 0.007). Those with CKD not on dialysis and treated with ACEI/ARB trended toward a lower hazard of dialysis initiation (HR 0.86, 95% CI 0.73-1.01, p = 0.06). The association with mortality did not differ by level of mineral metabolism marker (p for interaction >0.16); however, the relationship with dialysis initiation differed according to the median serum phosphorus level (p for interaction Conclusions: RAAS inhibition was associated with decreased all-cause mortality independent of disordered mineral metabolism among mostly male HOST subjects with advanced CKD and ESRD. However, among those with CKD not requiring dialysis, the renoprotection associated with RAAS inhibition was attenuated by higher serum phosphorus levels. Further studies are needed to confirm this association.

Cognitive impairment is common in advanced chronic kidney disease (CKD), but little is known about its relation with abnormalities in mineral metabolism. Methods: The longitudinal association between plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF-23) levels and cognitive function was assessed in 605 patients (67 ± 12 years) with advanced CKD not requiring dialysis (n = 247) or end-stage renal disease (ESRD; n = 358) who participated in the Homocysteine Study Cognitive Function Substudy (HOSTCOG)). Cognitive function was assessed using the Telephone Interview for Cognitive Status-modified (TICSm; mean follow-up 3.1 years) and associated with baseline mineral metabolite levels using linear regression analyses. Results: In unadjusted analyses, increasing log 1,25(OH)2D and decreasing log iPTH and FGF-23 levels were associated with worse cognitive status (p < 0.05). In fully adjusted multivariate analyses, the associations were no longer significant. Log 25(OH)D levels were not associated with cognitive function in unadjusted or adjusted analyses. Results were similar when analyzed by tertile or separately within CKD and ESRD groups. Conclusions: These results suggest that mineral metabolism dysregulation does not mediate the impairment in cognitive function common in advanced CKD.

Previous research has reported reduced serum 25-hydroxyvitamin D (25(OH)D) levels is associated with acute infectious illness. The relationship between vitamin D status, measured prior to acute infectious illness, with risk of community-acquired pneumonia (CAP) and sepsis has not been examined. Community-living individuals hospitalized with CAP or sepsis were age-, sex-, race-, and season-matched with controls. ICD-9 codes identified CAP and sepsis; chest radiograph confirmed CAP. Serum 25(OH)D levels were measured up to 15 months prior to hospitalization. Regression models adjusted for diabetes, renal disease, and peripheral vascular disease evaluated the association of 25(OH)D levels with CAP or sepsis risk. A total of 132 CAP patients and controls were 60 ± 17 years, 71% female, and 86% Caucasian. The 25(OH)D levels

Systolic BP and large elastic artery stiffness both increase with age and are reduced by dietary sodium restriction. Production of the natriuretic hormone marinobufagenin, an endogenous α1 Na+,K+-ATPase inhibitor, is increased in salt-sensitive hypertension and contributes to the rise in systolic BP during sodium loading.The hypothesis was that dietary sodium restriction performed in middle-aged/older adults (eight men and three women; 60 ± 2 years) with moderately elevated systolic BP (139 ± 2/83 ± 2 mmHg) would reduce urinary marinobufagenin excretion as well as systolic BP and aortic pulse-wave velocity (randomized, placebo-controlled, and crossover design). This study also explored the associations among marinobufagenin excretion with systolic BP and aortic pulse-wave velocity across conditions of 5 weeks of a low-sodium (77 ± 9 mmol/d) and 5 weeks of a normal-sodium (144 ± 7 mmol/d) diet.Urinary marinobufagenin excretion (weekly measurements; 25.4 ± 1.8 versus 30.7 ± 2.1 pmol/kg per day), systolic BP (127 ± 3 versus 138 ± 5 mmHg), and aortic pulse-wave velocity (700 ± 40 versus 843 ± 36 cm/s) were lower during the low- versus normal-sodium condition (all P0.05). Across all weeks, marinobufagenin excretion was related with systolic BP (slope=0.61, P0.001) and sodium excretion (slope=0.46, P0.001). These associations persisted during the normal- but not the low-sodium condition (both P0.005). Marinobufagenin excretion also was associated with aortic pulse-wave velocity (slope=0.70, P=0.02) and endothelial cell expression of NAD(P)H oxidase-p47phox (slope=0.64, P=0.006).These results show, for the first time in humans, that dietary sodium restriction reduces urinary marinobufagenin excretion and that urinary marinobufagenin excretion is positively associated with systolic BP, aortic stiffness (aortic pulse-wave velocity), and endothelial cell expression of the oxidant enzyme NAD(P)H oxidase. Importantly, marinobufagenin excretion is positively related to systolic BP over ranges of sodium intake typical of an American diet, extending previous observations in rodents and humans fed experimentally high-sodium diets.

Vascular calcification is highly prevalent in end-stage renal disease and independently predictive of future cardiovascular events and mortality. Calcification can occur in both the intimal and medial layers of vasculature, but medial calcification is the major form in end-stage renal disease. Medial calcification increases large elastic artery stiffness and pulse-pressure, promotes left ventricular hypertrophy, reduces perfusion of the coronary arteries, and ultimately promotes increased cardiovascular mortality via increased risk of myocardial infarction and heart failure. It results not from a passive deposition of calcium and phosphate due to increased circulating levels, but rather is an active cell-mediated process involving vascular smooth muscle cell apoptosis and vesicle release, a shift in the balance of inhibitors and promoters of vascular calcification, and vascular smooth muscle cell differentiation from a contractile to osteochondrogenic phenotype. This phenotypic shift requires phosphate, as well as the uptake of phosphate by the sodium-dependent phosphate cotransporter PiT-1, which is upregulated by proinflammatory cytokines and the uremic milieu. Further research is needed to determine if targeting these processes can ultimately reduce vascular calcification in this high cardiovascular risk population.

We sought to explore associations between serum 25-hydroxyvitamin D [25(OH)D] levels and non-alcoholic fatty liver disease [NAFLD] in an integrated healthcare delivery system in the U.S.Six hundred and seven NAFLD cases were randomly matched 1:1 with controls for age, sex, race and season of measurement. Conditional logistic regression was used to evaluate if serum 25(OH)D levels were associated with increased odds of NAFLD (diagnosed by ultrasound) after adjusting for body mass index and history of diabetes, renal, peripheral vascular and liver diseases (model 1) and also for hypertension (model 2). Mean (SD) serum 25(OH)D level was significantly lower in the group with NAFLD as compared with that in the matched control group (75 ± 17 vs. 85 ± 20 nmol/L [30 ± 7 vs. 34 ± 8 ng/mL], P0.001). Inadequate 25(OH)D status progressively increased the odds of NAFLD when classified categorically as sufficient (25(OH)D 75 nmol/L [30 ng/mL], reference group), insufficient (37-75 nmol/L [15-30 ng/mL]; adjusted odds ratio [OR]: 2.40, 95% confidence interval [CI]: 0.90-6.34) or deficient (37 nmol/L [15 ng/mL]; adjusted OR: 2.56, 95% CI: 1.27-5.19). When modeled as a continuous variable, increased log10 25(OH)D was inversely associated with the risk of prevalent NAFLD (adjusted OR: 0.25, 95% CI: 0.064-0.96, P=0.02).Compared with matched controls, patients with NAFLD have significantly decreased serum 25(OH)D levels, suggesting that low 25(OH)D status might play a role in the development and progression of NAFLD.

In the present study, we tested the hypothesis that age-associated vascular endothelial dysfunction is exacerbated by IFG (impaired fasting plasma glucose) and that regular aerobic exercise prevents this effect. Data were analysed from a cohort of 131 non-smoking men and women without overt clinical disease. Compared with young adult controls (age=24±1 years, n=29; values are means±S.E.M.), brachial artery FMD (flow-mediated dilation), a measure of conduit artery EDD (endothelium-dependent dilation), was 33% lower [7.93±0.33 against 5.27±0.37%Δ (% change), P45 min/day for ≥5 days/week, 62±1 years, n=23) compared with their non-exercising peers and only slightly less than young controls (P

Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging.

Background: Age and increasing systolic blood pressure (BP) are associated with vascular endothelial dysfunction, but the factors involved are incompletely understood. We tested the hypothesis that vascular endothelial function is related to dietary sodium intake among middle-aged and older adults (MA and O) with elevated systolic BP. Methods: Data were analyzed on 25 otherwise healthy adults aged 48—73 years with high normal systolic BP or stage I systolic hypertension (130—159 mmHg). Self-reported sodium intake was Results: Groups did not differ in other dietary factors, age, body weight and composition, BP, metabolic risk factors, physical activity and maximal aerobic capacity. Plasma concentrations of norepinephrine, endothelin-1, oxidized low-density lipoproteins (LDL), antioxidant status and inflammatory markers did not differ between groups. Brachial artery flow-mediated dilation (FMD) was 42% (mm Δ) to 52% (% Δ) higher in the low versus normal sodium group ( p < 0.05). In all subjects, brachial artery FMD was inversely related to dietary sodium intake (FMD mm Δr =—0.40, p < 0.05; %Δr =—0.53, p < 0.01). Brachial artery FMD was not related to any other variable. In contrast, endothelium-independent dilation did not differ between groups ( p ≥ 0.24) and was not related to sodium intake in the overall group ( p ≥ 0.29). Conclusions: Low sodium intake is associated with enhanced brachial artery FMD in MA and O with elevated systolic BP. These results suggest that dietary sodium restriction may be an effective intervention for improving vascular endothelial function in this high-risk group.

To determine whether impaired endothelium-dependent dilation (EDD) in older adults is associated with changes in the expression of major vasoconstrictor or vasodilator proteins in the vascular endothelium, endothelial cells (EC) were obtained from the brachial artery and peripheral veins of 56 healthy men, aged 18–78 yr. Brachial artery EC endothelin-1 (ET-1) [0.99 ± 0.10 vs. 0.57 ± 0.10 ET-1/human umbilical vein EC (HUVEC) intensity, P = 0.01] and serine 1177 phosphorylated endothelial nitric oxide synthase (PeNOS) (0.77 ± 0.09 vs. 0.44 ± 0.07 PeNOS/HUVEC intensity, P < 0.05) (quantitative immunofluorescence) were greater, and EDD (peak forearm blood flow to intrabrachial acetylcholine) was lower (10.2 ± 0.9 vs. 14.7 ± 1.7 ml·100 ml−1·min−1, P < 0.05) in older ( n = 18, 62 ± 1 yr) vs. young ( n = 15, 21 ± 1 yr) healthy men. EDD was inversely related to expression of ET-1 ( r = −0.39, P < 0.05). Brachial artery EC eNOS expression did not differ significantly with age, but tended to be greater in the older men (young: 0.23 ± 0.03 vs. older: 0.33 ± 0.07 eNOS/HUVEC intensity, P = 0.08). In the sample with venous EC collections, EDD (brachial artery flow-mediated dilation) was lower (3.50 ± 0.44 vs. 7.68 ± 0.43%, P < 0.001), EC ET-1 and PeNOS were greater ( P < 0.05), and EC eNOS was not different in older ( n = 23, 62 ± 1 yr) vs. young ( n = 27, 22 ± 1 yr) men. EDD was inversely related to venous EC ET-1 ( r = −0.37, P < 0.05). ET-1 receptor A inhibition with BQ-123 restored 60% of the age-related impairment in carotid artery dilation to acetylcholine in B6D2F1 mice (5–7 mo, n = 8; 30 mo, n = 11; P < 0.05). ET-1 expression is increased in vascular EC of healthy older men and is related to reduced EDD, whereas ET-1 receptor A signaling tonically suppresses EDD in old mice. Neither eNOS nor PeNOS is reduced with aging. Changes in ET-1 expression and bioactivity, but not eNOS, contribute to vascular endothelial dysfunction with aging.

The vascular endothelium may develop a proinflammatory profile with aging, but evidence is limited in humans. Expression of inflammatory proteins was determined in vascular endothelial cells (EC) obtained from peripheral veins of 24 young (23 +/- 1 years, mean +/- SE) and 36 older (63 +/- 1) healthy men and women using quantitative immunofluorescence. The older subjects had lower vascular endothelium-dependent dilation (forearm blood flow responses to acetylcholine, p0.05), and higher plasma concentrations of C-reactive protein, interleukin-6 (IL-6), and oxidized low-density lipoprotein (all p0.05), but not tumor necrosis factor-alpha (TNF-alpha). Total (O: 0.52 +/- 0.04 vs. Y: 0.33 +/- 0.05 NFkappaB/HUVEC intensity, p0.05) and nuclear (O: 0.59 +/- 0.04 vs. Y: 0.41 +/- 0.04) expression of nuclear factor kappa B p65 (NFkappaB), a proinflammatory gene transcription factor, was greater in EC from the older subjects (p0.05). EC expression of the inhibitor (of nuclear translocation) of NFkappaB (IkappaBalpha) was lower in the older subjects (O: 0.16 +/- 0.02 vs. Y: 0.24 +/- 0.03, p0.05), whereas IkappaB kinase (IkappaK) was not different. EC expression of the proinflammatory proteins IL-6 (O: 0.42 +/- 0.06 vs. Y: 0.29 +/- 0.03, p0.05), TNF-alpha (O: 0.52 +/- 0.06 vs. Y: 0.33 +/- 0.05, p0.05) and monocyte chemoattractant protein 1 (MCP-1) (O: 0.59 +/- 0.06 vs. Y: 0.38 +/- 0.02, p0.05) was greater in the older subjects, whereas cyclooxygenase 2 and the receptor for advanced glycation end-products did not differ. These findings indicate that impaired function with aging in healthy adults is associated with the development of a proinflammatory phenotype in the vascular endothelium that could be caused in part by reduced IkappaB-mediated inhibition of NFkappaB.

OBJECTIVE Aortic pulse-wave velocity (aPWV) increases with age and is a strong independent predictor of incident cardiovascular diseases (CVDs) in healthy middle-aged and older adults. aPWV is lower in middle-aged and older adults who perform regular aerobic exercise than in their sedentary peers. As exercise is associated with reduced systemic inflammation, we hypothesized that suppression of the pro-inflammatory transcription factor nuclear factor κ B (NFκB) may mediate this process. METHODS aPWV was measured in young sedentary [n = 10, blood pressure (BP) 108 ± 3/59 ± 2 mmHg; mean ± SEM], middle-aged and older sedentary (n = 9, 124 ± 7/73 ± 5 mmHg) and middle-aged and older aerobic exercise-trained (n = 12, 110 ± 4/67 ± 2 mmHg) healthy, nonhypertensive men and women. RESULTS Baseline aPWV increased with age [626 ± 14 (young sedentary) vs. 859 ± 49 (middle-aged and older sedentary) cm/s, P

Background and objectives Metabolomics is a relatively new field of “-omics” research, focusing on high-throughput identification of small molecular weight metabolites. Diet has both acute and chronic effects on metabolic profiles; however, alterations in response to dietary sodium restriction (DSR) are completely unknown. The goal of this study was to explore changes in urine metabolites in response to DSR, as well as their association with previously reported improvements in vascular function with DSR. Design, setting, participants, & measurements Using stored urine samples from a 10-week randomized placebo-controlled crossover study of DSR in 17 middle-aged/older adults (six men and 11 women; mean age 62±8 years) who had moderately elevated systolic BP (130–159 mmHg) and were otherwise healthy, a liquid chromatography/mass spectrometry–based analysis of 289 metabolites was performed. This study identified metabolites that were significantly altered between the typical (153±29 mmol/d) and low (70±29 mmol/d) sodium conditions, as well as their baseline (typical sodium) association with responsiveness to previously reported improvements in vascular endothelial function (brachial artery flow-mediated dilation) and large elastic artery stiffness (aortic pulse wave velocity). Results Of the 289 metabolites surveyed, 10 were significantly altered (nine were upregulated and one was downregulated) during the low sodium condition, and eight of these exceeded our prespecified clinically significant threshold of a >40% change. These metabolites were involved in biologic pathways broadly related to cardiovascular risk, nitric oxide production, oxidative stress, osmotic regulation, and metabolism. One metabolite, serine, was independently (positively) associated with previously reported improvements in the primary vascular outcome of brachial artery flow-mediated dilation. Conclusions This proof-of-concept study provides the first evidence that DSR is a stimulus that induces significant changes in urinary metabolomic profiles. Moreover, serine was independently associated with corresponding changes in vascular endothelial function after DSR. Larger follow-up studies will be required to confirm and further elucidate the metabolic pathways that are altered in response to DSR.

Fluid removal via ultrafiltration is a primary function of hemodialysis, and inadequate volume control is associated with significant morbidity and mortality among chronic dialysis patients. Treatment-to-treatment fluid removal goals are typically calculated on the basis of interdialytic weight gain and prescribed target weight. The clinical effect of frequent missed target weights is unclear. This study was designed to evaluate the associations of postdialysis weights above and below the prescribed target weight (separately) and outcomes.Data were taken from a national cohort of 10,785 prevalent, thrice-weekly, in-center hemodialysis patients dialyzing from 2005 to 2008 (median time at risk, 2.1 [25th percentile, 75th percentile] years) at a single dialysis organization. Patients were characterized as having an above target weight miss if their postdialysis weight was2 kg above target weight in at least 30% of baseline treatments (14.6% of cohort), or they were characterized as control otherwise. Below target weight miss characterization was analogous for patients with postdialysis weight2 kg below target weight (6.6% of cohort). Coprimary endpoints were all-cause and cardiovascular mortality.Above target weight miss in at least 30% of treatments (versus not) was associated with greater all-cause mortality (adjusted hazard ratio, 1.28; 95% confidence interval, 1.15 to 1.43); and below target weight miss in at least 30% of treatments (versus not) was associated with greater all-cause mortality (adjusted hazard ratio, 1.22; 95% confidence interval, 1.05 to 1.40). Both above and below target weight misses were also significantly associated with greater cardiovascular mortality. Secondary analyses demonstrated dose-response relationships between target weight misses and mortality. Results from sensitivity analyses considering the difference in postdialysis and target weights as a proportion of body weight were analogous to the primary results.Postdialysis weights2 kg above and below target weight are associated with higher all-cause and cardiovascular mortality. Consistent target weight achievement is a viable target for improving fluid management.

Smyth et al. examined the association between urinary sodium and potassium excretion and adverse renal outcomes in adults at high cardiovascular risk. They found no association between urinary sodium excretion and adverse renal outcomes, but a reduced odds of adverse renal outcomes with higher urinary potassium excretion. It will be important to ascertain whether this finding holds true in individuals free from vascular disease and diabetes, as well as in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this is only partially explained by traditional CVD risk factors. Vascular dysfunction is an important non-traditional risk factor, characterized by vascular endothelial dysfunction (most commonly assessed as impaired endothelium-dependent dilation [EDD]) and stiffening of the large elastic arteries. While various techniques exist to assess EDD and large elastic artery stiffness, the most commonly used are brachial artery flow-mediated dilation (FMDBA) and aortic pulse-wave velocity (aPWV), respectively. Both of these noninvasive measures of vascular dysfunction are independent predictors of future cardiovascular events in patients with and without kidney disease. Patients with CKD demonstrate both impaired FMDBA, and increased aPWV. While the exact mechanisms by which vascular dysfunction develops in CKD are incompletely understood, increased oxidative stress and a subsequent reduction in nitric oxide (NO) bioavailability are important contributors. Cellular changes in oxidative stress can be assessed by collecting vascular endothelial cells from the antecubital vein and measuring protein expression of markers of oxidative stress using immunofluorescence. We provide here a discussion of these methods to measure FMDBA, aPWV, and vascular endothelial cell protein expression.

Background Cardiovascular diseases such as atherosclerosis and vascular calcification are a major cause of death in patients with chronic kidney disease ( CKD ). Recently, the long‐awaited results of the Study of Heart and Renal Protection trial were reported. This large randomized clinical trial found that an extensive cholesterol‐lowering therapy through the combination of simvastatin and ezetimibe significantly reduced cardiovascular diseases in a wide range of patients with CKD . However, the mechanism by which this cholesterol‐lowering therapy reduces CKD ‐dependent vascular diseases remains elusive. The objective of the present study was to determine the contribution of the oxysterol‐induced pro‐apoptotic transcription factor CCAAT/enhancer‐binding protein homologous protein ( CHOP ) on the pathogenesis of CKD ‐dependent cardiovascular diseases through endoplasmic reticulum stress signaling. Methods and Results CKD increased levels of serum oxysterols such as 7‐ketocholesterol in human patients and ApoE −/− mice. Treatment with simvastatin plus ezetimibe strongly reduced levels of serum oxysterols and attenuated CKD ‐dependent atherosclerosis, vascular cell death, vascular calcification, and cardiac dysfunction. This therapy also reduced aortic endoplasmic reticulum stress induced by CKD . The short hairpin RNA ‐mediated knockdown of CHOP and activating transcription factor‐4 in vascular smooth muscle cells attenuated oxysterol‐induced mineralization, osteogenic differentiation, and endoplasmic reticulum stress. In addition, CHOP deficiency protected ApoE −/− mice from CKD ‐dependent vascular calcification, cardiac dysfunction, and vascular cell death. Conclusions These data reveal that the cholesterol‐lowering therapy of simvastatin plus ezetimibe attenuates CKD ‐dependent vascular diseases through a reduction of oxysterol‐mediated endoplasmic reticulum stress. CHOP plays a crucial role in the pathogenesis of CKD ‐dependent vascular calcification.

We performed a pilot study to test the hypothesis that acute oral ingestion of tetrahydrobiopterin (BH(4)), a key cofactor modulating vascular nitric oxide (NO) synthase activity, improves large elastic artery stiffness with aging in men.Healthy older (63 ± 2 years; n = 8) and young (age 25 ± 1 years; n = 6) men were studied 3 h after ingestion of BH(4) (10 mg·kg(-1) body weight) or placebo on separate days in a randomized, placebo-controlled, double-blind study.Baseline carotid artery compliance was 37% lower (0.17 ± 0.02 vs. 0.22 ± 0.02 mm/mm Hg·10(-1)) and β-stiffness was 42% higher (7.3 ± 1.1 vs. 4.2 ± 0.5 AU) in the older men (both P0.05). BH(4) ingestion markedly increased circulating BH(4) concentrations in both groups (17-19-fold, P0.05), but increased compliance (+39% to 0.23 ± 0.02 mm/mm Hg·10(-1), P0.01) and decreased β-stiffness index (-27% to 5.3 ± 0.7 AU, P0.01) only in the older men. BH(4) also reduced carotid systolic blood pressure (SBP) in the older men (P0.05).These preliminary results support the possibility that limited BH(4) bioavailability contributes to impaired carotid artery compliance in healthy older men. Further studies are needed to determine if increasing BH(4) bioavailability though oral BH(4) supplementation may have therapeutic efficacy for improving large elastic artery compliance and reducing central SBP with aging.

We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was lower ( P 29 ng/mL; 61±1 years of age; n=22) subjects, whereas endothelium-independent dilation (brachial dilation to sublingual nitroglycerine) did not differ ( P =0.45). Among all subjects, brachial flow-mediated dilation was positively related to serum 25(OH)D (%Δ: r =0.35; P r =−0.06; P =0.61), the active form of vitamin D. Vascular endothelial cell expression of the proinflammatory transcription factor nuclear factor κB was greater in deficient versus sufficient subjects (0.59±0.07 versus 0.44±0.05; P P P r =−0.62; P P

Resting whole leg blood flow and vascular conductance decrease linearly with advancing age in healthy adult men. The potential role of age-related increases in oxidative stress in these changes is unknown. Resting leg blood flow during saline and ascorbic acid infusion was studied in 10 young (25 ± 1 yr) and 11 older (63 ± 2 yr) healthy normotensive men. Plasma oxidized LDL, a marker of oxidative stress, was greater in the older men ( P < 0.05). Absolute resting femoral artery blood flow at baseline (iv saline control infusion) was 25% lower in the older men (238 ± 25 vs. 316 ± 38 ml/min; P < 0.05), and it was inversely related to plasma oxidized LDL ( r = −0.56, P < 0.01) in all subjects. Infusion of supraphysiological concentrations of ascorbic acid increased femoral artery blood flow by 37% in the older men (to 327 ± 52 ml/min; P < 0.05), but not in the young men (352 ± 41 ml/min; P = 0.28), thus abolishing group differences ( P = 0.72). Mean arterial blood pressure was greater in the older men at baseline (86 ± 4 vs. 78 ± 2 mmHg; P < 0.05), but it was unaffected by ascorbic acid infusion ( P ≥ 0.70). As a result, the lower baseline femoral artery blood flow in the older men was mediated solely by a 32% lower femoral artery vascular conductance ( P < 0.05). Baseline femoral vascular conductance also was inversely related to plasma oxidized LDL ( r = −0.65, P < 0.01). Ascorbic acid increased femoral vascular conductance by 36% in the older men ( P < 0.05) but not in the young men ( P = 0.31). In conclusion, ascorbic acid infused at concentrations known to scavenge reactive oxygen species restores resting femoral artery blood flow in healthy older adult men by increasing vascular conductance. These results support the hypothesis that oxidative stress plays a major role in the reduced resting whole leg blood flow and increased leg vasoconstriction observed with aging in men.

Cystatin C was introduced as a potential alternative or supplement to the estimation of glomerular filtration rate (GFR) using creatinine. Although cystatin C is well supported as a better predictor of outcomes than creatinine, its reflection of actual renal function compared with creatinine is widely debated. A new study by Rule et al. asserts that cystatin-C-based estimated GFR is biased by non-GFR-associated risk factors for chronic kidney disease.

ObjectivesThis study sought to determine the efficacy of dietary sodium restriction (DSR) for improving vascular endothelial dysfunction in middle-aged/older adults with moderately elevated systolic blood pressure (SBP) (130–159 mm Hg) and the associated physiological mechanisms.BackgroundVascular endothelial dysfunction develops with advancing age and elevated SBP, contributing to increased cardiovascular risk. DSR lowers BP, but its effect on vascular endothelial function and mechanisms involved are unknown.MethodsSeventeen subjects (11 men and 6 women; mean age, 62 ± 7 years) completed a, randomized crossover study of 4 weeks of both low (DSR) and normal sodium intake. Vascular endothelial function (endothelium-dependent dilation; EDD), nitric oxide (NO)/tetrahydrobiopterin (BH4) bioavailability, and oxidative stress-associated mechanisms were assessed following each condition.ResultsUrinary sodium excretion was reduced by ∼50% (to 70 ± 30 mmol/day), and conduit (brachial artery flow-mediated dilation [FMDBA]) and resistance (forearm blood flow responses to acetylcholine [FBFACh]) artery EDD were 68% and 42% (peak FBFACh) higher following DSR (p < 0.005). Low sodium markedly enhanced NO-mediated EDD (greater ΔFBFACh with endothelial NO synthase inhibition) without changing endothelial NO synthase expression/activation (Ser 1177 phosphorylation), restored BH4 bioactivity (less ΔFMDBA with acute BH4), abolished tonic superoxide suppression of EDD (less ΔFMDBA and ΔFBFACh with ascorbic acid infusion), and increased circulating superoxide dismutase activity (all p < 0.05). These effects were independent of ΔSBP. Other subject characteristics/dietary factors and endothelium-independent dilation were unchanged.ConclusionsDSR largely reversed both macro- and microvascular endothelial dysfunction by enhancing NO and BH4 bioavailability and reducing oxidative stress. Our findings support the emerging concept that DSR induces “vascular protection” beyond that attributable to its BP-lowering effects.