Adipose and height growth through childhood and blood pressure status in a large prospective cohort study.

Raised blood pressure (BP) is the world's leading mortality risk factor. Childhood BP substantially predicts adult levels, and although both prenatal and postnatal growth influence it, their relative importance is debated. In a longitudinal study (Avon Longitudinal Study of Parents and Children) of 12 962 healthy children, we aimed to assess the relative contribution of different growth periods and of standardized measures of height versus weight-for-height (an adiposity marker) to BP at age 10 years. Conditional growth modeling was used in the 3230 boys and 3346 girls with BP measurements. Systolic BP was inversely associated with birth weight and weight-for-height but not length (-0.33, -0.27, and -0.12 mm Hg · SD(-1); P=0.003, 0.035, and 0.35, respectively). In infancy, weight, weight-for-height, and height gains were all positively associated with systolic BP (0.90, 0.41, and 0.82 mm Hg · SD(-1), respectively; all P<0.001). After infancy, all of the growth modalities were positively associated with systolic BP (weight, 1.91; weight-for-height, 1.56; height, 1.20 mm Hg · SD(-1); all P<0.001). Similar but weaker associations were found with diastolic BP. Although BP at 10 years was associated with both prenatal and early postnatal growth, their influence was small compared with that of later growth. Because BP ranking relative to the population is substantially determined in the first decade of life, a focus on strategies to reduce the development of adiposity from infancy onward, rather than an emphasis on the nutrition and weight of mothers and infants, should bring greater reductions in population BP.

Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.

BACKGROUND: Preeclampsia is a life-threatening pregnancy syndrome of uncertain origin. To elucidate the pathogenesis, we evaluated the temporal relationships between changes in vascular function and circulating biomarkers of angiogenic activity before and after the onset of preeclampsia and gestational hypertension. METHODS AND RESULTS: Maternal mean arterial pressure, uterine artery pulsatility index, brachial artery flow-mediated dilatation, and serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin were prospectively measured in 159 women from 10 weeks gestation until 12 weeks postpartum. At 10 to 17 weeks, women who developed preterm preeclampsia had lower serum PlGF (P=0.003), higher soluble endoglin (P=0.006), and higher sFlt-1:PlGF ratio (P=0.005) compared with women who later developed term preeclampsia, gestational hypertension, or normotensive pregnancy. At 10 to 17 weeks, mean arterial pressure inversely correlated with serum PlGF (r=-0.19, P=0.02); at 18 to 25 weeks, with soluble endoglin (r=0.18, P=0.02); and at 26 to 33 weeks, with sFlt-1 (r=0.28, P<0.001). At 23 to 25 weeks, uterine artery pulsatility index correlated with serum soluble endoglin (r=0.19, P=0.02) and sFlt-1 levels (r=0.17, P=0.03). Flow-mediated dilatation was higher during a pregnancy with gestational hypertension compared with preeclampsia (P=0.001). Twelve weeks postpartum, serum PlGF was higher in women who had a hypertensive pregnancy compared with a normotensive pregnancy (P<0.001). CONCLUSIONS: These observations support a role for placenta-derived angiogenic biomarkers in the control of maternal vascular resistance of preeclampsia. Gestational hypertension develops differently, with a hyperdynamic circulation and angiogenic biomarker profile similar to normotensive pregnancy. Larger studies of unselected women are needed to ascertain whether measures of these angiogenic biomarkers assist with the prediction and prognosis of preeclampsia and whether postpartum measures of serum PlGF have a role in predicting future cardiovascular disease.

Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC).

AIMS: To assess the feasibility and reproducibility of non-invasive vascular assessment in a childhood population setting and identify the determinants of vascular phenotype in early life. METHODS AND RESULTS: We studied 7557 children (age 9.8-12.3 years) participating in the Avon Longitudinal Study of Parents and Children (ALSPAC). Six research technicians underwent a 5-month training protocol to enable study of brachial artery endothelial function by flow-mediated dilatation (FMD) and arterial stiffness by carotid to radial pulse wave velocity (PWV) and brachial distensibility [distensibility coefficient (DC)]. Reproducibility studies were performed at the beginning, the middle, and the end of the study. A blinded repeat evaluation of a random selection of 3% of the cohort was also undertaken throughout the study. The effect of anthropometric and environmental factors on each measure was examined. Successful measures were obtained in 88, 95, and 87% of the studied children for FMD, PWV, and DC, respectively. The coefficients of variation between technicians for FMD, PWV, and DC were 10.5, 4.6, and 6.6% at the beginning of the study and reached 7.7, 4.1, and 10% at the end. Baseline vessel diameter and gender were important determinants of all the vascular measures, with a small effect of room and skin temperatures on FMD and PWV. Boys consistently had lower FMD and DC and higher PWV measures (P < 0.01 for all). CONCLUSION: Reproducible, high-quality assessments of vascular structure and function in children can be made on a large scale in field studies by suitably trained non-specialist operators. This study provides an invaluable resource for assessing the impact of early influences, genetic, and environmental factors on arterial phenotype.

Endothelial response to childhood infection: the role of mannose-binding lectin (MBL).

OBJECTIVE: To assess the influence of mannose-binding lectin (MBL) genotype on endothelial function in the presence and absence of infection in childhood. METHODS: We studied 2176 children aged 10 years drawn from the Avon Longitudinal Study of Parents and Children. Endothelial function was assessed by flow mediated dilatation (FMD). Exon 1 and promoter polymorphisms in the MBL gene were determined by heteroduplexing procedures. Children were classified as AA (wild type) AO (heterozygotes) and OO (homozygotes). RESULTS: During the vascular assessment, 544 children presented with current or recent (<2 weeks) infection (INF). FMD was reduced in the INF group compared to controls (10% reduction in FMD, p<0.001). MBL genotype was not associated with FMD in controls, although a relationship with the degree of impairment during INF was observed (8.0%, 7.6% and 26.6% lower FMD compared to controls for groups AA, AO, OO respectively, p<0.05). After multivariate analysis, OO was associated with reduced FMD in the INF group (odds ratio 2.95 [1.33, 6.52], p<0.001). CONCLUSION: Homozygosity for MBL variant alleles is associated with greater impairment in FMD during infection in childhood. This suggests a gene-environment interaction operating in early life that may have relevance for the initiation and progression of atherosclerosis.

Endothelial function predicts progression of carotid intima-media thickness.

BACKGROUND: Endothelial dysfunction develops early and has been shown to predict the development of clinical complications of atherosclerosis. However, the relationship between early endothelial dysfunction and the progression of arterial disease in the general population is unknown. We investigated endothelial dysfunction, risk factors, and progression of carotid intima-media thickness (cIMT) in late-middle-aged individuals at low to intermediate cardiovascular risk in a prospective study between 1997 and 2005. METHODS AND RESULTS: Brachial artery flow-mediated dilatation and cIMT were measured in 213 nonsmoking British civil servants recruited from a prospective cohort (Whitehall II study). Participants (age, 45 to 66 years) were free of clinical cardiovascular disease and diabetes mellitus. Risk factors and Framingham Risk Score were determined at baseline. cIMT was repeated 6.2+/-0.4 years later. At baseline, age, blood pressure, low-density lipoprotein cholesterol, and Framingham Risk Score correlated with cIMT. However, only flow-mediated dilatation, not risk factors or Framingham Risk Score, was associated with average annual progression of cIMT. This relationship remained significant after adjustment for risk factors whether entered as separate variables or as Framingham Risk Score. Further adjustment for waist circumference, triglycerides, and employment grade had no significant effect. CONCLUSIONS: Systemic endothelial function was associated with progression of preclinical carotid arterial disease over a 6-year period and was more closely related to cIMT changes than conventional risk factors. Thus, the relationship between endothelial dysfunction and adverse outcome is likely to be due not only to destabilization of established disease in high-risk populations but also to its impact on the evolution of the atherosclerotic substrate. Flow-mediated dilatation testing provides an integrated vascular measure that may aid the prediction of structural disease evolution and represents a potential short- to intermediate-term outcome measure for evaluation of preventive treatment strategies.

Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.

BACKGROUND: Vascular calcification is associated with increased morbidity and mortality in stage V chronic kidney disease, yet its early pathogenesis and initiating mechanisms in vivo remain poorly understood. To address this, we quantified the calcium (Ca) load in arteries from children (10 predialysis, 24 dialysis) and correlated it with clinical, biochemical, and vascular measures. METHODS AND RESULTS: Vessel Ca load was significantly elevated in both predialysis and dialysis and was correlated with the patients' mean serum Ca x phosphate product. However, only dialysis patients showed increased carotid intima-media thickness and increased aortic stiffness, and calcification on computed tomography was present in only the 2 patients with the highest Ca loads. Importantly, predialysis vessels appeared histologically intact, whereas dialysis vessels exhibited evidence of extensive vascular smooth muscle cell (VSMC) loss owing to apoptosis. Dialysis vessels also showed increased alkaline phosphatase activity and Runx2 and osterix expression, indicative of VSMC osteogenic transformation. Deposition of the vesicle membrane marker annexin VI and vesicle component mineralization inhibitors fetuin-A and matrix Gla-protein increased in dialysis vessels and preceded von Kossa positive overt calcification. Electron microscopy showed hydroxyapatite nanocrystals within vesicles released from damaged/dead VSMCs, indicative of their role in initiating calcification. CONCLUSIONS: Taken together, this study shows that Ca accumulation begins predialysis, but it is the induction of VSMC apoptosis in dialysis that is the key event in disabling VSMC defense mechanisms and leading to overt calcification, eventually with clinically detectable vascular damage. Thus the identification of factors that lead to VSMC death in dialysis will be of prime importance in preventing vascular calcification.

Measurement of endothelial function and its clinical utility for cardiovascular risk.

Over the past two decades, the central role of the endothelium in the initiation, progression, and clinical sequelae of atherosclerosis has been increasingly recognized. Assessment of the pathobiology of the endothelium and its ability to act as a potential therapeutic target remains an area of active research interest. Whilst endothelial function has been shown to be a marker for risk of cardiovascular events in high-risk groups, there remains considerable debate about the most appropriate way to assess this. We discuss the different clinical methods to assess endothelial function, focusing on flow-mediated dilatation (FMD) of the brachial artery, highlighting the importance of using a standardized methodology, as well as discussing the clinical limitations of using FMD in individuals.

Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation.

OBJECTIVES: Our aim was to determine reproducibility of the flow-mediated dilation (FMD) response profile, and discriminatory ability of the components. BACKGROUND: Brachial FMD is widely used to study conduit artery endothelial function. Automated B-mode image edge detection (B-ED) provides a full response profile. Reproducibility and biological relevance of these additional components have not been fully explored. METHODS: Forty-two healthy adults underwent FMD using B-ED repeated at fixed time intervals up to 3 months. The FMD profile was assessed for diameter changes, area under the curve, and time course. Measures were compared in 25 adults with hypercholesterolemia, 25 subjects with diabetes, and 50 matched control subjects. RESULTS: The maximum change in FMD was the most reproducible (coefficient of variation = 9.8%, 10.6%, 6.6%, and 9.2% at 4 to 6 h, 1 week, 1 month, and 3 months, respectively). Most of the variability occurred between subjects rather than within. All FMD measures except time course were significantly reduced in hypercholesterolemia and diabetes. Power curves were generated to indicate the appropriate number of subjects for parallel and crossover study designs. CONCLUSIONS: Maximum FMD percentage change from baseline is the most reproducible of the response curve measures and best identifies those with risk factors. Flow-mediated dilation measured by B-ED is robust and practical to assess the effect of interventions on endothelial function in clinical trials.

A bimodal association of vitamin D levels and vascular disease in children on dialysis.

In addition to its classical role in calcium-phosphate homeostasis, vitamin D has anti-inflammatory effects that may influence vascular disease. This study examined the impact of vitamin D levels on the vascular phenotype in 61 children who had been on dialysis for >or=3 mo and in 40 age-matched control subjects. All dialysis patients were prescribed daily oral 1-alpha hydroxyvitamin D(3). 92% of patients were deficient in 25-hydroxyvitamin D [25(OH)D]. 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were low in 36% and high in 11% of patients. There was a weak correlation between 1 alpha-hydroxyvitamin D(3) dosage and 1,25(OH)(2)D levels. Both carotid intima-media thickness and calcification scores showed a U-shaped distribution across 1,25(OH)(2)D levels: patients with both low and high 1,25(OH)(2)D had significantly greater carotid intima-media thickness (P < 0.0001) and calcification (P = 0.0002) than those with normal levels. Low 1,25(OH)(2)D levels were associated with higher high-sensitivity C-reactive protein (P < 0.0001). Calcification was most frequently observed in patients with the lowest 1,25(OH)(2)D and the highest high-sensitivity C-reactive protein. In contrast, 25(OH)D levels did not correlate with any vascular measure. In conclusion, both low and high 1,25(OH)(2)D levels are associated with adverse morphologic changes in large arteries, and this may be mediated through the effects of 1,25(OH)(2)D on calcium-phosphate homeostasis and inflammation. For optimization of strategies to protect the vasculature of dialysis patients, careful monitoring of 1,25(OH)(2)D levels may be required.

Mineral metabolism and vascular damage in children on dialysis.

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for > or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.

A dose-response study of hormone replacement in young hypogonadal women: effects on intima media thickness and metabolism.

OBJECTIVE: Young hypogonadal women appear to have an increased risk of cardiovascular disease. We studied the influence of increasing doses of hormone replacement therapy (HRT) on markers of metabolism and vascular physiology. DESIGN: Nine-month sequential dose-ranging study. PATIENTS: A total of 25 young hypogonadal women (Turner Syndrome, n = 14; 46,XX gonadal dysgenesis, n = 9), hypogonadotrophic hypogonadism (n = 2), mean age 31.9 years (range 18.5-42.2). All subjects sequentially received oral 17beta-oestradiol 1,2 and 4 mg daily in a cyclical formulation for 12 weeks each. MEASUREMENTS: Metabolic markers and vascular physiology measurements to assess intima media thickness (IMT); arterial stiffness: pulse wave velocity (PWV) and augmentation index (AIx); endothelial function: flow-mediated dilatation (FMD). Results Increasing doses of oestrogen resulted in a reduction in IMT (0.63 +/- 0.06 vs. 0.58 +/- 0.06 vs. 0.56 +/- 0.06 mm at 1 mg, 2 mg and 4 mg 17beta-oestradiol, respectively, P = 0.001). RESULTS: were similar in women with Turner Syndrome and normal karyotype. High-density lipoprotein (HDL) cholesterol concentrations increased (1.9 +/- 0.4 vs. 2.0 +/- 0.5 vs. 2.2 +/- 0.4 mmol/l, P = 0.001) and plasma glucose (4.8 +/- 0.4 vs. 4.7 +/- 0.3 vs. 4.6 +/- 0.6 mmol/l, P = 0.038) decreased slightly with the increasing dose of HRT. There was no correlation between the changes in IMT and HDL. Increasing HRT dose had no significant impact on blood pressure, weight, other lipid parameters, insulin, C-reactive protein, interleukin-6 and fibrinogen concentrations or FMD, PWV and AIx. CONCLUSIONS: Increasing doses of HRT result in a reduction in carotid IMT in young hypogonadal women, along with increased serum HDL and decreased plasma glucose. This study raises the possibility that exogenous oestrogen may be cardioprotective in young women, but this observation needs to be balanced against a prothrombotic effect which is predominant in postmenopausal women.

Non-invasive assessment of endothelial function: which technique?

OBJECTIVES: The purpose of this study was to compare 3 non-invasive techniques for assessment of endothelial function in adults and children and evaluate their utility in acute inflammation. BACKGROUND: Endothelial dysfunction is a key early event in pre-clinical atherosclerosis. Flow-mediated dilation (FMD), although the established technique, is expensive and technically demanding. Measurements of vascular responses to inhaled salbutamol by pulse wave analysis (PWA) or pulse contour analysis (PCA) are potential alternatives. METHODS: Sixteen adults (mean age 28 years, range 18 to 39) and 16 children (mean age 13 years, range 7 to 17) underwent concurrent vascular function testing on 2 occasions with ultrasound, PWA, and PCA. Eighteen men were also studied before and after typhoid vaccination. RESULTS: Reproducibility of FMD was high in adults and children (coefficient of variation [CV] = 7.1 and 6.3, respectively). Salbutamol responses were more variable with PWA (adults CV = 11.5, children CV = 17.1) and PCA particularly in children (adults CV = 18.2, children CV = 36.3). Flow-mediated dilation (p < 0.001) and PWA with salbutamol (p = 0.03) responses fell after typhoid vaccination, and PCA (p = 0.7) was unchanged. CONCLUSIONS: Vascular dysfunction during acute inflammation can be measured by FMD and by PWA with salbutamol. Flow-mediated dilation is less variable than PWA. Variability of PCA makes this technique currently unsuited to serial measures of endothelial function in children. Flow-mediated dilation remains the most reproducible method.

Delayed blood pressure recovery after psychological stress is associated with carotid intima-media thickness: Whitehall psychobiology study.

OBJECTIVE: Delayed blood pressure (BP) recovery after psychological stress is associated with low socioeconomic status (SES) and prospectively with increases in clinic BP. We tested whether poststress BP recovery was related to carotid atherosclerosis. METHODS AND RESULTS: Psychophysiological stress testing was performed with a healthy subgroup of the Whitehall II epidemiological cohort, and recovery systolic BP was monitored 40 to 45 minutes after stressful behavioral tasks. Carotid ultrasound scanning was conducted on 136 men and women (aged 55.3+/-2.7 years) 3 years after stress testing. Participants were divided into those whose systolic BP had returned to baseline in the recovery period (adequate recovery, n=37), and those whose BP remained elevated (delayed recovery, n=99). Systolic BP stress responses did not differ in the 2 groups. Carotid intima-media thickness (IMT) was associated with delayed recovery in lower SES (means 0.78 versus 0.65 mm) but not higher SES participants (means 0.75 versus 0.74 mm) after adjustment for age, gender, baseline systolic BP, and resting BP, smoking, body mass and fasting cholesterol at the time of ultrasound scanning (P=0.010). CONCLUSIONS: Variations in poststress recovery reflect dysfunction of biological regulatory processes, and may partly mediate psychosocial influences on cardiovascular disease.

Circadian variation in endothelial function is attenuated in postmenopausal women.

OBJECTIVE: The present study was undertaken to investigate the possible existence of an endogenously generated circadian rhythm in endothelial function in women and whether this rhythm is altered after the menopause. METHODS: Healthy non smoking women (11 pre-menopausal and 13 postmenopausal women) were studied during a 22 h period under constant routine conditions; endothelium-dependent (flow-mediated dilation (%FMD)) and -independent (glyceryl-trintrate (GTN)-mediated) function was assessed every 2 and 4 h, respectively, by high-resolution ultrasound of the brachial artery. RESULTS: %FMD and %GTN was significantly higher in pre-menopausal women (9.9+/-1.0%FMD (mean+/-S.E.M.); 18.2+/-1.8%GTN; P<0.01) compared with postmenopausal women (6.5+/-0.5%FMD; 11.5+/-1.6%GTN). A significant day-night variation in %FMD was observed pre-menopausal women (day 9.2+/-0.8%; night 10.4+/-1%; P<0.05) with an attenuated rhythm in postmenopausal women (day 6.8+/-0.6%; night 6.0+/-0.4%). CONCLUSIONS: The findings show a circadian rhythm in %FMD in pre-menopausal women, which disappears after the menopause. The reduction in %FMD and an absence of a day-night variation in %FMD in postmenopausal women may have important implications for the incidence of coronary heart disease in women after the menopause.

Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy.

BACKGROUND: Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children. METHODS AND RESULTS: We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects (P<0.001). Among the HIV-infected children, age and treatment were significantly associated with increased IMT. Children exposed to PIs had greater IMT compared with both non-PI-treated children and untreated children (P=0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects (P=0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3; P<0.001) for children exposed to PIs compared with untreated children and by a mean of 1.8% (95% CI, 0.01 to 3.5; P=0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT. CONCLUSIONS: HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention.

Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction.

CONTEXT: Women with Turner syndrome (TS) have an increased cardiovascular mortality rate from both structural and ischemic heart disease, especially aortic dissection. OBJECTIVE: We hypothesized that TS women have a fundamental arterial wall defect that may be due to genetic factors or estrogen deficiency. DESIGN, SETTING, AND PATIENTS: TS women (n = 93) were compared with normal controls (n = 25) and women with 46,XX primary amenorrhea (PA) (n = 11) with a similar history of estrogen deficiency. Clinical parameters, aortic root diameter, extraaortic arterial structure [common carotid (CD), brachial artery diameter, and carotid intima-media thickness (IMT)], arterial stiffness (pulse-wave velocity, augmentation index), and endothelial function (flow-mediated dilatation) were assessed. MAIN OUTCOME MEASURES: These included arterial diameters and vascular physiology parameters. RESULTS: Differences in arterial structure were observed among TS, normal controls, and 46,XX PA women: IMT (0.61 +/- 0.07 vs. 0.55 +/- 0.06 vs. 0.60 +/- 0.05 mm, respectively; P < 0.001), CD (5.71 +/- 0.64 vs. 5.27 +/- 0.34 vs. 5.22 +/- 0.38 mm; P < 0.001), and brachial artery diameter (3.29 +/- 0.44 vs. 3.06 +/- 0.36 vs. 2.97 +/- 0.30 mm; P = 0.006). Aortic root diameter was greater in TS than normal control women. TS status, height, weight, and IMT were independently associated with increased CD after multivariate adjustment (P < 0.05). TS status, age, diastolic blood pressure, and CD remained independently associated with increased IMT after multivariate adjustment (P < 0.05). Pulse-wave velocity and flow-mediated dilatation were similar among the three groups. CONCLUSION: Women with TS have greater IMT and conduit artery diameters than normal controls. Similarly, increased IMT in TS and 46,XX PA women suggests that estrogen deficiency contributes to intimal thickening. Interventional studies are required to determine the extent to which blood pressure and estrogen deficiency may be appropriate therapeutic targets to reduce cardiovascular risk in TS.

Endothelial dysfunction in childhood infection.

BACKGROUND: Atherosclerosis begins in early life, and endothelial dysfunction is recognized as a key initiating event in the development of atherosclerosis. Although infection has been implicated in endothelial dysfunction and atherogenesis, the impact of acute common childhood infections on the vascular endothelium is unknown. METHODS AND RESULTS: We studied 600 children aged 10 years drawn from the Avon Longitudinal Study of Parents and Children. The children were divided into 3 groups: those with current acute infection (AI; n=135; 73 boys and 62 girls); a convalescent group with infection in the past 2 weeks (n=166; 78 boys and 88 girls), and a healthy control group (n=299; 131 boys and 168 girls). Endothelial function was determined in all subjects by high-resolution ultrasound to measure brachial artery flow-mediated dilation (FMD) and was expressed as the percentage change in diameter from baseline after reactive hyperemia. FMD was repeated in 40 children in the AI group and 50 in the control group after a mean interval of 1 year. FMD was lower in both the AI group (6.3+/-2.7%, mean+/-SD) and the convalescent group (8.1+/-3.1%) than in the control group (9.7+/-2.5%; P<0.001 for both). The observed differences in FMD remained after adjustment for potential confounding variables. At the repeat visit, FMD was unchanged in controls (P=0.85) but improved in the AI group (P<0.001). CONCLUSIONS: Acute infection in childhood is associated with impaired endothelium-dependent vasodilation. These findings support a potential role for previously unsuspected extrinsic inflammatory stimuli in the pathogenesis of early atherosclerosis.

Social and psychosocial influences on inflammatory markers and vascular function in civil servants (the Whitehall II study).

Social position and psychosocial factors are associated with coronary disease, but the underlying pathophysiologic mechanisms remain unclear. In a sample of 283 nonsmokers, we found that social position was inversely associated with interleukin-6 and C-reactive protein and that participants with mild depression had impaired endothelial function.

Vitamin C improves resistance but not conduit artery endothelial function in patients with chronic renal failure.

BACKGROUND: Chronic renal failure is associated with impaired endothelium-dependent vasodilation and accelerated atherogenesis. To examine whether endogenous reactive oxygen species (ROS) modify endothelial function in renal failure, we evaluated the effect of the antioxidant vitamin C on endothelium-dependent responses in both the conduit and resistance vasculature of subjects with severe renal impairment. METHODS: Endothelial function of the forearm resistance vasculature was assessed using plethysmography to measure the dilator response to intra-arterial acetylcholine (Ach) (25 to 100 nmol/min). Endothelial function of radial and brachial arteries was assessed using vascular ultrasound to measure the dilator response to flow during reactive hyperemia [flow-mediated dilatation (FMD)]. Studies were performed before and after administration of vitamin C by intra-arterial infusion (25 mg/min) in 33 predialysis patients or by intravenous infusion (3 g) in 17 hemodialysis patients. RESULTS: Parenteral administration of vitamin C resulted in a 100-fold increase (intra-arterial studies) and a 4.5-fold increase (intravenous studies) in serum antioxidant activity. Vitamin C administration increased the dilator response to ACh in resistance vessels (P = 0.01), but did not alter the dilator response to flow in conduit vessels of either dialysis (P = 0.3) or predialysis subjects (P = 0.8). In the presence of the nitric oxide (NO) synthase inhibitor NGmonomethyl-L-arginine (L-NMMA), there was no effect of vitamin C on resistance vessel endothelial function. In all cases the dilator response to the endothelium-independent dilators was unaffected by vitamin C. CONCLUSION: Acute administration of vitamin C reduces oxidant stress in renal failure and improves NO-mediated resistance vessel dilatation.

Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure.

BACKGROUND: Cardiovascular disease is a major cause of mortality amongst patients with chronic renal failure (CRF). L-arginine has been used to improve endothelial function by increasing nitric oxide (NO) bioavailability and in animal models this in turn has attenuated the progression of atherosclerosis. We examined whether dietary L-arginine supplementation improved endothelial function in children with CRF. METHODS: A randomized, double-blind, placebo-controlled, crossover trial of L-arginine was conducted in 21 normotensive children aged 11.5 +/- 3 (7 to 17) years with CRF (GFR 27.4 +/- 13.2 mL/min/1.73 m(2)) in whom endothelial dysfunction had previously been demonstrated. We examined the effect of L-arginineon the endothelial response to shear stress (NO-dependent) using a non-invasive technique of high-resolution ultrasound. Each subject was studied before and after 4 weeks of L-arginine (2.5 g/m(2) or 5 g/m(2) x 3/day) or placebo, separated by a rest period of 4 weeks. Brachial artery diameter was measured at rest, during increased flow (endothelial-dependent dilation) and after 25 microg of glyceryl trinitrate (endothelial-independent dilation) at each visit. RESULTS: After oral L-arginine, plasma L-arginine levels rose from 82 +/- 20 to 179 +/- 110 micromol/L (P < 0.001). No significant change in endothelial-dependent dilation during L-arginine (7.96 +/- 2.35 to 7.71 +/- 3.22%; P> 0.05) or placebo (8.2 +/- 2.89 to 8.3 +/- 3.14%; P> 0.05) was noted. There was no change in endothelial-independent dilation. CONCLUSION: Endothelial function was not improved with L-arginine, suggesting that dietary supplementation is not a useful clinical approach in children with CRF.