Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Overweight across the life course and adipokines, inflammatory and endothelial markers at age 60-64 years: evidence from the 1946 birth cohort.

BACKGROUND/OBJECTIVES: There is growing evidence that early development of obesity increases cardiovascular risk later in life, but less is known about whether there are effects of long-term excess body weight on the biological drivers associated with the atherosclerotic pathway, particularly adipokines, inflammatory and endothelial markers. This paper therefore investigates the influence of overweight across the life course on levels of these markers at retirement age. SUBJECTS/METHODS: Data from the Medical Research Council National Survey of Health and Development (n=1784) were used to examine the associations between overweight status at 2, 4, 6, 7, 11, 15, 20, 26, 36, 43, 53 and 60-64 years (body mass index (BMI)⩾25 kg m(-2) for adult ages and gender-specific cut-points for childhood ages equivalent to BMI⩾25 kg m(-2)) and measurements of adipokines (leptin and adiponectin), inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6)) and endothelial markers (E-selectin, tissue plasminogen activator (t-PA) and von Willebrand factor) at 60-64 years. In addition, the fit of different life course models (sensitive periods/accumulation) were compared using partial F-tests. RESULTS: In age- and sex-adjusted models, overweight at 11 years and onwards was associated with higher leptin, CRP and IL-6 and lower adiponectin; overweight at 15 years and onwards was associated with higher E-selectin and t-PA. Associations between overweight at all ages earlier than 60-64 with leptin, adiponectin, CRP and IL-6 were reduced but remained apparent after adjustment for overweight at 60-64 years; whereas those with E-selectin and t-PA were entirely explained. An accumulation model best described the associations between overweight across the life course with adipokines and inflammatory markers, whereas for the endothelial markers, the sensitive period model for 60-64 years provided a slightly better fit than the accumulation model. CONCLUSIONS: Overweight across the life course has a cumulative influence on adipokines, inflammatory and possibly endothelial markers. Avoidance of overweight from adolescence onwards is likely important for cardiovascular disease prevention.

Preliminary study of video imaging of blood vessels in tissues lining the gingival sulcus in periodontally healthy individuals.

BACKGROUND AND OBJECTIVE: The aim of this study was to obtain in vivo images of the microcirculation in tissues lining the gingival crevice in periodontally healthy volunteers and to assess the repeatability of the parameters measured. MATERIAL AND METHODS: Video microscopy images of the microcirculation of tissues lining the gingival crevice were obtained from 20 periodontally healthy volunteers. Images were obtained with a single 1 mm diameter 1 pitch gradient index lens with a high numerical aperture and with a plain glass lens and illumination with a green 525 nm light-emitting diode and recorded using a video microscope. RESULTS: The morphological features of the vessels (including vessel diameter, vessel density, loops, branches, dilated vessels) were similar to those described previously in other mammals. The Kappa values for the assessment of morphology of the vessels using the gradient index lens range from 0.83 for branching to 0.91 for dilated and using the glass lens 0.47 for branching and 0.38 for dilated. CONCLUSIONS: This novel system allowed for a consistent and repeatable assessment of the gingival microvasculature. However, there was some evidence of possible pressure artefacts in those cases where the measurements of separation between vessels exceeded 150 µm.

Geographical Variation in Underlying Social Deprivation, Cardiovascular and Other Comorbidities in Patients with Potentially Curable Cancers in England: Results from a National Registry Dataset Analysis.

AIMS: To describe the prevalence of cardiovascular disease (CVD), multiple comorbidities and social deprivation in patients with a potentially curable cancer in 20 English Cancer Alliances. MATERIALS AND METHODS: This National Registry Dataset Analysis used national cancer registry data and CVD databases to describe rates of CVD, comorbidities and social deprivation in patients diagnosed with a potentially curable malignancy (stage I-III breast cancer, stage I-III colon cancer, stage I-III rectal cancer, stage I-III prostate cancer, stage I-IIIA non-small cell lung cancer, stage I-IV diffuse large B-cell lymphoma, stage I-IV Hodgkin lymphoma) between 2013 and 2018. Outcome measures included observation of CVD prevalence, other comorbidities (evaluated by the Charlson Comorbidity Index) and deprivation (using the Index of Multiple Deprivation) according to tumour site and allocation to Cancer Alliance. Patients were allocated to CVD prevalence tertiles (minimum: <33.3rd percentile; middle: 33.3rd to 66.6th percentile; maximum: >66.6th percentile). RESULTS: In total, 634 240 patients with a potentially curable malignancy were eligible. The total CVD prevalence for all cancer sites varied between 13.4% (CVD n = 2058; 95% confidence interval 12.8, 13.9) and 19.6% (CVD n = 7818; 95% confidence interval 19.2, 20.0) between Cancer Alliances. CVD prevalence showed regional variation both for male (16-26%) and female patients (8-16%) towards higher CVD prevalence in northern Cancer Alliances. Similar variation was observed for social deprivation, with the proportion of cancer patients being identified as most deprived varying between 3.3% and 32.2%, depending on Cancer Alliance. The variation between Cancer Alliance for total comorbidities was much smaller. CONCLUSION: Social deprivation, CVD and other comorbidities in patients with a potentially curable malignancy in England show significant regional variations, which may partly contribute to differences observed in treatments and outcomes.

Are there socioeconomic inequalities in cardiovascular risk factors in childhood, and are they mediated by adiposity? Findings from a prospective cohort study.

BACKGROUND: Socioeconomic gradients in adiposity were not present during childhood for previous generations, but have emerged in contemporary children. It is unknown whether this translates to socioeconomic gradients in associated cardiovascular risk factors in children, with consequent implications for inequalities in coronary heart disease (CHD) and diabetes when these children reach adulthood. METHODS: Using data from 7772 participants aged 10-years from the Avon Longitudinal Study of Parents and Children, we examined the association between maternal education and a large number of cardiovascular risk factors (cholesterol, triglycerides, high-density lipoprotein, apolipoprotein, adiponectin, leptin, C-reactive protein (CRP), interleukin-6 (IL-6) and systolic and diastolic blood pressure), and examined whether inequalities were mediated by adiposity, measured by dual energy X-ray absorptiometry (DXA)-assessed total fat mass. RESULTS: There were socioeconomic differences in a number of the cardiovascular risk factors (apolipoprotein B, systolic and diastolic blood pressure, CRP, leptin and IL-6). Inequalities were greater in girls than boys. Inequalities in CRP and leptin were completely mediated by adiposity. Inequalities in other cardiovascular risk factors were partially mediated by adiposity. CONCLUSION: This study showed important socioeconomic inequalities in adiposity and associated cardiovascular risk factors in a contemporary UK population of 10-year-old children. Differences between contemporary children and previous generations in the socioeconomic patterning of cardiovascular risk factors suggest future adults may have greater inequalities in diabetes and CHD than current adults. These findings highlight the importance of interventions aimed at preventing obesity in childhood, particularly among those of lower socioeconomic position.

Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level.

Familial hypercholesterolemia is associated with premature atherosclerosis. Since endothelial dysfunction is an early event in atherogenesis, we used a noninvasive method to assess endothelial function in the systemic arteries of 30 children aged 7-17 yr (median 11) with familial hypercholesterolemia (2 homozygotes, 28 heterozygotes, total cholesterol 240-696 mg/dl) and 30 healthy age- and sex-matched controls. Using high resolution ultrasound, the diameter of the superficial femoral artery was measured at rest, in response to reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual glyceryltrinitrate (causing endothelium-independent vasodilation). Flow-mediated dilation was present in the controls (7.5 +/- 0.7%) but was impaired or absent in the hypercholesterolemic children (1.2 +/- 0.4%, P < 0.0001). Total cholesterol was inversely correlated with flow-mediated dilation (r = -0.61, P < 0.0001). In the hypercholesterolemic children, flow-mediated dilation was inversely related to the lipoprotein(a) level (r = -0.61, P = 0.027) but not to other lipid fractions. Glyceryltrinitrate-induced dilation was present in all subjects but was lower in the hypercholesterolemia group (10.0 +/- 0.6% vs 12.4 +/- 0.8%, P = 0.023). Thus, impaired endothelium-dependent dilation is present in children with familial hypercholesterolemia as young as 7 yr of age and the degree of impairment is related to the lipoprotein(a) level.

Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.

In hypercholesterolemic rabbits, oral L-arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29+/-5 (19-40) years, with known endothelial dysfunction and LDL-cholesterol levels of 238+/-43 mg/dl. Each subject was studied before and after 4 wk of L-arginine (7 grams x 3/day) or placebo powder, with 4 wk washout, in a randomized double-blind crossover study. Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation). After oral L-arginine, plasma L-arginine levels rose from 115+/-103 to 231+/-125 micromol/liter (P<0.001), and EDD improved from 1.7+/-1.3 to 5.6+/-3.0% (P<0.001). In contrast there was no significant change in response to glyceryl trinitrate. After placebo there were no changes in endothelium-dependent or independent vascular responses. Lipid levels were unchanged after L-arginine and placebo. Dietary supplementation with L-arginine significantly improves EDD in hypercholesterolemic young adults, and this may impact favorably on the atherogenic process.

Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study.

BACKGROUND: The long-term excess risk of death associated with diabetes following acute myocardial infarction is unknown. We determined the excess risk of death associated with diabetes among patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after adjustment for comorbidity, risk factors and cardiovascular treatments. METHODS: Nationwide population-based cohort (STEMI n=281 259 and NSTEMI n=422 661) using data from the UK acute myocardial infarction registry, MINAP, between 1 January 2003 and 30 June 2013. Age, sex, calendar year and country-specific mortality rates for the populace of England and Wales (n=56.9 million) were matched to cases of STEMI and NSTEMI. Flexible parametric survival models were used to calculate excess mortality rate ratios (EMRR) after multivariable adjustment. This study is registered at ClinicalTrials.gov (NCT02591576). RESULTS: Over 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes, there were 187 875 (26.7%) deaths. Overall, unadjusted (all cause) mortality was higher among patients with than without diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a 72% and 67% excess risk of death following STEMI (EMRR 1.72, 95% CI 1.66 to 1.79) and NSTEMI (1.67, 1.63 to 1.71). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity (EMRR 1.52, 95% CI 1.46 to 1.58 vs 1.45, 1.42 to 1.49), risk factors (1.50, 1.44 to 1.57 vs 1.33, 1.30 to 1.36) and cardiovascular treatments (1.56, 1.49 to 1.63 vs 1.39, 1.36 to 1.43). CONCLUSIONS: At index acute myocardial infarction, diabetes was common and associated with significant long-term excess mortality, over and above the effects of comorbidities, risk factors and cardiovascular treatments.

Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors.

BACKGROUND: Atherosclerosis develops from childhood, but the determinants of this preclinical stage remain uncertain. We examined the relations of classic coronary risk factors, adiposity and its associated metabolic disturbances, to arterial distensibility (a marker of early arterial disease) in 13- to 15-year-olds, some of whom had previously been studied at ages 9 to 11 years. METHODS AND RESULTS: Brachial artery distensibility was measured by a noninvasive ultrasound technique in 471 British children in whom measures of adiposity, blood pressure, fasting blood lipids, and insulin had been made. All adiposity measures showed strong graded inverse relationships with distensibility. Inverse associations with distensibility were also observed for insulin resistance (homeostasis model assessment), diastolic pressure, C-reactive protein, and the number of metabolic syndrome components present, which had a graded relation to distensibility. Total and LDL cholesterol levels were also inversely related to distensibility, but less strongly than adiposity; homocysteine had no relation to distensibility. Although the relations of total and LDL cholesterol and diastolic pressure to distensibility had been present at 9 to 11 years of age, those of adiposity and insulin resistance were only apparent at 13 to 15 years. CONCLUSIONS: Adiposity and its metabolic consequences are associated with adverse changes in the arterial wall by the teenage years. The graded relation with increasing adiposity was stronger than that for cholesterol and was seen at body mass index levels well below those considered to represent "obesity." This emphasizes the importance of population-based strategies to control adiposity and its metabolic consequences in the young.

Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function.

An endothelial nitric oxide synthase (eNOS) gene polymorphism (Glu298Asp) has been associated with cardiovascular disease. We investigated whether carriage of the polymorphism was associated with functional changes in the endothelium, and how genotype altered the harmful and beneficial impact of environmental influences on the endothelium. Endothelium-dependent, flow-mediated brachial artery dilatation (FMD) and endothelium-independent dilatation response to glyceryl trinitrate were measured using high-resolution ultrasound in 248 subjects (131 female, 117 male, aged 20 to 28) genotyped for the Glu298Asp polymorphism. Vascular function was compared between genotype groups and interactions with the proatherogenic risk factor, smoking, and the antiatherogenic influence of n-3 fatty acids (n-3FA) were investigated. Vascular function was not related to genotype in the group as a whole or within sexes. However, among males, smoking was associated with lower FMD in Asp298 carriers (nonsmokers 0.125+/-0.085 mm versus smokers 0.070+/-0.060 mm, P=0.006) but not in Glu298 homozygotes (nonsmokers 0.103+/-0.090 mm versus smokers 0.124+/-0.106, P=0.5). In the whole group, n-3FA levels were positively related to FMD in Asp298 carriers (reg coeff=0.023 mm/%, P=0.04, r=0.20) but not in Glu298 homozygotes (reg coeff=-0.019 mm/%, P=0.1). These differences between genotype groups were significant in interaction models. The Glu298Asp polymorphism is associated with differences in endothelial responses to both smoking and n-3 FA in healthy young subjects. These findings raise the possibility of genotype-specific prevention strategies in cardiovascular disease.

Geographic variation in the treatment of non-ST-segment myocardial infarction in the English National Health Service: a cohort study.

OBJECTIVES: To investigate geographic variation in guideline-indicated treatments for non-ST-elevation myocardial infarction (NSTEMI) in the English National Health Service (NHS). DESIGN: Cohort study using registry data from the Myocardial Ischaemia National Audit Project. SETTING: All Clinical Commissioning Groups (CCGs) (n=211) in the English NHS. PARTICIPANTS: 357 228 patients with NSTEMI between 1 January 2003 and 30 June 2013. MAIN OUTCOME MEASURE: Proportion of eligible NSTEMI who received all eligible guideline-indicated treatments (optimal care) according to the date of guideline publication. RESULTS: The proportion of NSTEMI who received optimal care was low (48 257/357 228; 13.5%) and varied between CCGs (median 12.8%, IQR 0.7-18.1%). The greatest geographic variation was for aldosterone antagonists (16.7%, 0.0-40.0%) and least for use of an ECG (96.7%, 92.5-98.7%). The highest rates of care were for acute aspirin (median 92.8%, IQR 88.6-97.1%), and aspirin (90.1%, 85.1-93.3%) and statins (86.4%, 82.3-91.2%) at hospital discharge. The lowest rates were for smoking cessation advice (median 11.6%, IQR 8.7-16.6%), dietary advice (32.4%, 23.9-41.7%) and the prescription of P2Y12 inhibitors (39.7%, 32.4-46.9%). After adjustment for case mix, nearly all (99.6%) of the variation was due to between-hospital differences (median 64.7%, IQR 57.4-70.0%; between-hospital variance: 1.92, 95% CI 1.51 to 2.44; interclass correlation 0.996, 95% CI 0.976 to 0.999). CONCLUSIONS: Across the English NHS, the optimal use of guideline-indicated treatments for NSTEMI was low. Variation in the use of specific treatments for NSTEMI was mostly explained by between-hospital differences in care. Performance-based commissioning may increase the use of NSTEMI treatments and, therefore, reduce premature cardiovascular deaths. TRIAL REGISTRATION NUMBER: NCT02436187.

Regional wall motion and abnormalities of electrical depolarization and repolarization in patients after surgical repair of tetralogy of Fallot.

BACKGROUND: Abnormal depolarization-repolarization in patients with repaired tetralogy of Fallot (TOF) is a risk factor for malignant ventricular tachycardia and sudden death. It is unclear whether ECG abnormalities are associated with abnormal regional right ventricular (RV) function. METHODS AND RESULTS: Seventy-four patients (37 patients <18 and 37 >18 years old) who had had TOF repair at 4.0 years old (0.1 to 47 years old) were examined when they were 18.7 years old (1.7 to 61.1 years old), as were 112 control subjects with normal hearts. Regional function was evaluated with tissue Doppler imaging of the RV and left ventricular (LV) free wall and the septum. Myocardial velocities were sampled continuously from base to apex. Synchronous ECG was analyzed for QRS, QT, and JT duration and QRS, QT, and JT dispersion. All 74 TOF patients had normal LV myocardial velocities. Forty-eight patients (24 patients <18 and 24 >18 years old) had reversed myocardial velocities in diastole in the RV free wall, which were associated with reversed systolic myocardial velocities in 22 and additional reverse diastolic myocardial velocities in the septum in 19. Those 48 patients had a longer QRS duration (151+/-31 versus 124+/-27 ms) and greater QRS (47+/-18 versus 29+/-12 ms), QT (73+/-27 versus 52+/-22 ms), and JT (96+/-31 versus 67+/-35 ms) dispersion. Compared with normal control subjects, all 74 TOF patients had decreased systolic and diastolic myocardial velocities and a longer isovolumic relaxation time. CONCLUSIONS: RV wall-motion abnormalities are a common finding late after TOF repair and are associated with repolarization-depolarization abnormalities. These data further underscore a likely mechanoelectrical interaction as an important part of the pathogenesis of RV disease in these patients.

Impact of low birth weight and cardiovascular risk factors on endothelial function in early adult life.

BACKGROUND: Low birth weight is related to increased risk of coronary heart disease in adults and recently has been associated with vascular endothelial dysfunction in children. We investigated whether the relation between birth weight and endothelial function was still present in early adult life and whether there was an interaction with emerging risk factors. METHODS AND RESULTS: In 315 adults (165 women, 150 men, aged 20 to 28 years), high-resolution ultrasound was used to determine endothelium-dependent and -independent vascular responses of the brachial artery. Vascular measures were related to classic risk factors (smoking history, lipid profile, blood pressure, fasting insulin, exercise capacity, body mass index, and combined risk score) and birth weight. Low birth weight was associated with reduced flow-mediated dilation (coefficient=0.18 kg(-1), 95% CI 0.004 to 0.35, P:=0.04) but not with endothelium-independent dilation. The difference in flow-mediated dilation between the top and bottom fifths of birth weight was the same as between smokers and nonsmokers. Increasing levels of acquired risk factors overwhelmed the association, and there was a significant interaction of risk score with the birth weight-endothelial function relation (coefficient of interaction term [birth weightxrisk score] = -0.12, 95% CI -0.22 to -0.03, P:=0.01). CONCLUSIONS: Low birth weight is associated with endothelial dysfunction in young adults. This is most marked in individuals with lower risk factor profiles and may be relevant to the pathogenesis of atherosclerosis in later life.

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure?

BACKGROUND: Accelerated vascular disease is common in chronic renal failure (CRF) and accounts for significant mortality and morbidity. Elevated homocysteine levels may contribute by an effect on endothelial function. METHODS AND RESULTS: We performed a double-blind placebo-controlled randomized crossover trial of folic acid at 5 mg/m2 in 25 normotensive children 12+/-3 (7 to 17) years of age with CRF (glomerular filtration rate 26.8+/-13.2 mL/min per 1.73 m2) of noninflammatory etiology. Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period. The effect of folic acid on homocysteine levels, LDL oxidation, and both endothelial-dependent and -independent vascular function were measured. After oral folic acid, serum folate levels rose from 11.7+/-4.25 to 635+/-519 microg/L (P=0.001), red cell folate levels rose from 364+/-195 to 2891+/-2623 microg/L (P<0.001), and total homocysteine levels fell from 10.28+/-4.16 to 8.62+/-2.32 micromol/L (P=0.03). In addition, there was a significant improvement in flow-mediated dilatation (FMD) (endothelial-dependent dilatation) from 7.21+/-2.8% to 8.47+/-3.01% (P=0.036) with no change in response to glyceryl trinitrate (endothelial-independent dilatation). There was no significant change in FMD or glyceryl trinitrate during the placebo phase. There was, however, no significant difference in final FMD after placebo or folic acid. Lag times for LDL oxidation were prolonged during the treatment phase (58.4+/-18.7 to 68.1+/-25.9 minutes, P=0.01). CONCLUSION: Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation.

Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation.

BACKGROUND: The pulsatile nature of pulmonary blood flow is important for shear stress-mediated release of endothelium-derived nitric oxide (NO) and lowering pulmonary vascular resistance (PVR) by passive recruitment of capillaries. Normal pulsatile flow is lost or markedly attenuated after Fontan-type operations, but to date, there are no data on basal pulmonary vascular resistance and its responsiveness to exogenous NO at late follow-up in these patients. METHODS AND RESULTS: We measured indexed PVR (PVRI) using Fick principle to calculate pulmonary blood flow, with respiratory mass spectrometry to measure oxygen consumption, in 15 patients (median age, 12 years; range, 7 to 17 years; 12 male, 3 female) at a median of 9 years after a Fontan-type operation (6 atriopulmonary connections, 7 lateral tunnels, 2 extracardiac conduits). The basal PVRI was 2.11+/-0.79 Wood unit (WU) times m2 (mean+/-SD) and showed a significant reduction to 1.61+/-0.48 (P=0.016) after 20 ppm of NO for 10 minutes. The patients with nonpulsatile group in the pulmonary circulation dropped the PVRI from 2.18+/-0.34 to 1.82+/-0.55 (P<0.05) after NO inhalation. CONCLUSIONS: PVR falls with exogenous NO late after Fontan-type operation. These data suggest pulmonary endothelial dysfunction, related in some part to lack of pulsatility in the pulmonary circulation because of altered flow characteristics. Therapeutic strategies to enhance pulmonary endothelial NO release may have a role in these patients.

Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients.

BACKGROUND: In the Fontan circulation, pulmonary and systemic vascular resistances are in series. The implications of this unique arrangement on infradiaphragmatic venous physiology are poorly understood. METHODS AND RESULTS: We studied the effects of respiration and gravity on infradiaphragmatic venous flows in 20 normal healthy volunteers (control) and 48 Fontan patients (atriopulmonary connection [APC] n=15, total cavopulmonary connection [TCPC] n=30). Hepatic venous (HV), subhepatic inferior vena caval (IVC), and portal venous (PV) flow rates were measured with Doppler ultrasonography during inspiration and expiration in both the supine and upright positions. The inspiratory-to-expiratory flow rate ratio was calculated to reflect the effect of respiration, and the supine-to-upright flow rate ratio was calculated to assess the effect of gravity. HV flow depended heavily on inspiration in TCPC compared with both control and APC subjects (inspiratory-to-expiratory flow rate ratio 3.4, 1.7, and 1.6, respectively; P:<0.0001). Normal PV flow was higher in expiration, but this effect was lost in TCPC and APC patients (inspiratory-to-expiratory flow rate ratio 0.8, 1.0, and 1.1, respectively; P:=0.01). The respiratory influence on IVC flow was the same in all groups. Gravity decreased HV flow more in APC than in TCPC patients (supine-to-upright flow rate ratio 3.2 versus 2.1, respectively; P:<0.04) but reduced PV flow equally in all groups. CONCLUSIONS: Gravity and respiration have important influences on infradiaphragmatic venous return in Fontan patients. Although gravity exerts a significant detrimental effect on lower body venous return, which is more marked in APC than in TCPC patients, the beneficial effects of respiration in TCPC patients are mediated primarily by an increase in HV flow. These effects may have important short- and long-term implications for the hemodynamics of the Fontan circulation.

Cholesterol and arterial distensibility in the first decade of life: a population-based study.

BACKGROUND: Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years. METHODS AND RESULTS: A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient -11.8 microm. mmol(-1). L(-1), P=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (-12.9 microm. mmol(-1). L(-1), P=0. 005 and -36.9 microm/mmol/L, P=0.01). HDL and triglyceride levels showed no consistent association with distensibility. CONCLUSIONS: LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.

Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo.

BACKGROUND: Endothelial dysfunction leading to neutrophil infiltration of tissues has been implicated in tissue injury caused by ischemia-reperfusion (IR). Tissue injury during IR can be reduced by prior ischemic preconditioning (IPC). In humans, it is unclear whether endothelial dysfunction occurs during IR or whether IPC offers protection against endothelial dysfunction and inflammatory cell activation. We studied the effects of experimental IR on endothelial and neutrophil function in the human forearm in vivo and examined the protection afforded by IPC. METHOD AND RESULTS: The forearm was made ischemic for 20 minutes by inflating a blood pressure cuff to 200 mm Hg. We assessed endothelial function of conduit (radial artery flow-mediated dilation) and resistance vessels (blood flow responses to intra-arterial infusion of the endothelium-dependent dilator acetylcholine) in healthy volunteers before and after IR. IR reduced flow-mediated dilation of the radial artery at 15 minutes of reperfusion (7.7+/-1.5% to 3.5+/-0.9%) and the dilator response of resistance vessels to acetylcholine at 15, 30, and 60 minutes of reperfusion. IR did not reduce the dilator response of the radial artery to glyceryltrinitrate and only caused a small reduction of glyceryltrinitrate-induced dilation of resistance vessels at 60 minutes of reperfusion. IR caused an increase in neutrophil CD11b expression and platelet-neutrophil complexes in the circulating blood. IPC (three 5-minute episodes of ischemia) before IR prevented endothelial dysfunction and neutrophil activation. CONCLUSIONS: A clinically relevant period of ischemia-reperfusion causes profound and sustained endothelial dysfunction and systemic neutrophil activation. IPC attenuates both of these effects in humans.

Mental stress induces transient endothelial dysfunction in humans.

BACKGROUND: Mental stress has been linked to increased morbidity and mortality in coronary artery disease and to atherosclerosis progression. Experimental studies have suggested that damage to the endothelium may be an important mechanism. METHODS AND RESULTS: Endothelial function was studied in 10 healthy men (aged 50. 4+/-9.6 years) and in 8 non-insulin-dependent diabetic men (aged 52. 0+/-7.2 years). Brachial artery flow-mediated dilation (FMD, endothelium dependent) and response to 50 microg of sublingual glyceryl trinitrate (GTN, endothelium independent) were measured noninvasively by use of high-resolution ultrasound before and after (30, 90, and 240 minutes) a standardized mental stress test. The same protocol without mental stress was repeated on a separate occasion in the healthy men. In healthy subjects, FMD (5.0+/-2.1%) was significantly (P:<0.01) reduced at 30 and 90 minutes after mental stress (2.8+/-2.3% and 2.3+/-2.4%, respectively) and returned toward normal after 4 hours (4.1+/-2.0%). Mental stress had no effect on the response to GTN. In the repeated studies without mental stress, FMD did not change. The diabetic subjects had lower FMD than did the control subjects (3.0+/-1.5% versus 5.0+/-2.1%, respectively; P:=0.02) but showed no changes in FMD (2.7+/-1.1% after 30 minutes, 2.8+/-1.9% after 90 minutes, and 3.1+/-2.3% after 240 minutes) or GTN responses after mental stress. CONCLUSIONS: These findings suggest that brief episodes of mental stress, similar to those encountered in everyday life, may cause transient (up to 4 hours) endothelial dysfunction in healthy young individuals. This might represent a mechanistic link between mental stress and atherogenesis.