Marietta Charakida

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.

Endothelial function and inflammation in coronary artery disease

Evidence supports the central role of endothelium and inflammation in all phases of the atherosclerotic process. Clinical studies have shown their prognostic potential for the development of ischaemic events and for adverse outcome after acute coronary syndromes. Reduction in inflammatory levels and improving endothelial function by traditional and novel treatment strategies were associated with a proportional reduction in cardiovascular events. However, randomised controlled trials are required to explore further whether drugs targeting the inflammatory process and endothelial function will constitute a reasonable adjunctive treatment for patients with coronary artery disease.

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.

Vascular Abnormalities, Paraoxonase Activity, and Dysfunctional HDL in Primary Antiphospholipid Syndrome

CONTEXT Accelerated atherosclerosis has been described in antiphospholipid syndrome, but the vascular abnormalities and the underlying mechanisms remain unclear. OBJECTIVES To compare vascular structure and function in patients with positive antiphospholipid antibodies (aPL) with controls and to assess their relationship with paraoxonase activity. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 77 women with positive antiphospholipid antibodies from a lupus outpatient clinic in London, England (90% of the eligible population) and 77 controls matched on frequency basis for age and cardiovascular risk factors between June 2006 and April 2009. Carotid intima media thickness (CIMT), flow-mediated dilatation, pulse wave velocity, and paraoxonase activity were measured in all patients. Anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL) were examined. MAIN OUTCOME MEASURES CIMT, pulse wave velocity, flow-mediated dilatation, and paraoxonase. RESULTS Women with aPL had greater CIMT and pulse wave velocity compared with controls (mean [SD], 0.75 [0.16] vs 0.64 [0.09] mm; 95% confidence interval [CI], -0.14 to -0.06; P < .001; and 9.2 [1.6] vs 8.5 [1.8] m/s; 95% CI, -1.14 to -0.06; P = .04) and lower flow-mediated dilatation (6.2% [4.1%] vs 9.6% [4.2%]; 95% CI, 2.02%-4.69%; P < .001). Paraoxonase activity was lower in women with aPL vs controls (median [interquartile range], 91.2 [64.3-105.1] vs 103.0 [80.5-111.5] micromol p-nitrophenol/L/serum/min; 95% CI, 0.004-0.007; P = .005) and was inversely associated with CIMT and pulse wave velocity in women with aPL (standardized beta coefficient = -0.4 and -0.3, respectively; P < .05 for both), but not in the control group. High-density lipoprotein from women with aPL inhibited endothelial nitric oxide production in human aortic endothelial cells, in contrast with controls. The beneficial effects of HDL from women with aPL on vascular cell adhesion molecule 1 expression, superoxide production, and monocyte adhesion following activation of human aortic endothelial cells were largely blunted. CONCLUSIONS Compared with controls, women with aPL had greater functional and structural arterial abnormalities, which were associated with lower activity of paraoxonase. In patients with aPL, HDL reduced nitric oxide bioavailability and had impaired anti-inflammatory and antioxidant properties.

Adiposity and cardiovascular risk factors in a large contemporary population of pre-pubertal children

AIMS to examine the associations of several markers of adiposity and a wide range of cardiovascular risk factors and biomarkers in pre-pubertal children. METHODS AND RESULTS four measures of adiposity,body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry (DXA)-determined fat mass, and leptin concentration, were available in up to 7589 children aged 8.8-11.7 (9.9 mean) years from the Avon Longitudinal Study of Parents and Children (ALSPAC). Thirteen per cent of boys and 18.8% of girls were overweight, and 5.3% of boys and 5% of girls were obese. Body mass index was highly correlated with waist circumference (r = 0.91), DXA fat mass (r = 0.87), and leptin concentration (r = 0.75), and all had similar associations with cardiovascular risk factors. A 1 kg/m(2) greater BMI was associated with 1.4 mmHg (95% CI 1.25-1.44) higher systolic blood pressure (BP). In 5002 children, a 1 kg/m(2) greater BMI was associated with a 0.05 mmol/L (95% CI 0.036-0.055) higher non-high-density lipoprotein (HDL) cholesterol and 0.03 mmol/L (95% CI -0.034 to -0.025) lower HDL cholesterol. There were also graded associations with apolipoproteins A1 and B, interleukin-6, and C-reactive protein. Comparing children who were obese with those who were normal weight, the odds ratio for hypertension was 10.7 (95% CI 7.2-15.9) for boys and 13.5 (95% CI 9.4-19.5) for girls. CONCLUSION in pre-pubertal UK children, overweight/obesity is common and has broadly similar associations with BP, HDL cholesterol, and non-HDL cholesterol to those observed in adults. Future research should evaluate whether effective interventions to maintain healthy weight in childhood could have important benefits for adult cardiovascular risk.

Role of NADPH Oxidase in Endothelial Ischemia/Reperfusion Injury in Humans

Background— Reactive oxygen species have been implicated in the pathogenesis of ischemia/reperfusion (IR) injury. Recent studies suggest that NADPH oxidase may be a source of ROS during IR. Using an in vivo model of endothelial IR injury in the arm, we compared the response to IR in healthy volunteers with that in patients with chronic granulomatous disease. These patients have a molecular lesion in a subunit of NADPH oxidase that renders the enzyme inactive. Methods and Results— Flow-mediated dilatation was used to assess endothelial function in patients with X-linked (NOX2) or autosomal (p47) chronic granulomatous disease. IR injury was induced by 20 minutes of upper limb ischemia followed by reperfusion. Flow-mediated dilatation was determined before IR and after 20 minutes of reperfusion. The response to IR in chronic granulomatous disease patients was compared with that in age- and sex-matched healthy control subjects. Flow-mediated dilatation was expressed as mean and compared statistically with mixed linear models. IR caused a significant reduction in flow-mediated dilatation in control subjects (−5.1%; 95% confidence interval, 6.3 to 3.%; P<0.001; n=11). IR had no effect on endothelial function in NOX2-chronic granulomatous disease patients (−0.9; 95% confidence interval, −2.1 to 0.3; P=0.12; n=11). Similarly, IR-induced reduction in flow-mediated dilatation was not observed in p47-chronic granulomatous disease patients (−1.5%; 95% confidence interval, −3.1 to 0.2; P=0.08; n=6) in contrast to healthy control subjects (−6.5%; 95% confidence interval, −8.2 to −4.9%; P<0.001; n=6). Conclusions— These data indicate, for the first time in humans in vivo, that reactive oxygen species produced by NADPH oxidase are determinants of endothelial function after IR injury in humans. These findings have implications for the design of strategies to limit clinical IR injury.

Childhood Obesity and Vascular Phenotypes A Population Study

OBJECTIVES This study sought to assess the associations of childhood adiposity with vascular phenotype in pre-pubertal children. BACKGROUND The early-life metabolic consequences have consistently been demonstrated in obese children, but the time course and development of any vascular changes remain largely unexplored. METHODS A total of 6,576 children age 10 to 11 years from the ALSPAC (Avon Longitudinal Study of Parents and Children) were studied. Childhood overweight and obesity were based on body mass index contemporary to vascular measures and supported by other adiposity measures, including fat mass and waist circumference on dual-energy x-ray absorptiometry. Heart rate, blood pressure, flow-mediated dilation in the brachial artery, and carotid to radial pulse wave velocity were measured in all children. RESULTS Overweight and obese children had higher heart rates (mean 72.4 ± 11 beats/min and 74.6 ± 12.2 beats/min vs. 71.7 ± 11 beats/min) and systolic blood pressures (mean 106.3 ± 9.1 mm Hg and 108 ± 10.2 mm Hg vs. 103.6 ± 9 mm Hg) compared with normal-weight peers. However, obese children had greater brachial diameters and resting and hyperemic blood flow, marginally increased endothelial function (higher flow-mediated dilation: mean 8.2 ± 3.2% vs. 8.1 ± 3.3%), and lower arterial stiffness (pulse wave velocity: mean 6.99 ± 1.0 m/s vs. 7.05 ± 1.23 m/s) compared with normal-weight children. These findings were not explained by metabolic differences. CONCLUSIONS Greater childhood adiposity is associated with adverse cardiometabolic risk factors, but with no evidence of vascular damage at age 9 to 11 years. This could represent physiological adaptation to the hyperemic state of adiposity in childhood.

Adipose and Height Growth Through Childhood and Blood Pressure Status in a Large Prospective Cohort Study

Raised blood pressure (BP) is the worlds 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.

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.

Childhood origins of arterial disease.

Purpose of review The present article reviews the importance of classical and novel risk factors that present in childhood, track into adult life and contribute to arterial disease. The value of noninvasive techniques that can assist in characterization of preclinical atherosclerotic changes as intermediate phenotypes is also discussed. Recent findings Noninvasive functional and structural techniques are now available and provide the opportunity to characterize early arterial disease long before cardiovascular complications present. By using these techniques, it has been possible to quantify the impact of conventional and novel cardiovascular risk factors seen in childhood on the development of preclinical atherosclerotic changes. Scientific interest has recently widened to include not only study of mechanisms and biomarkers of injury but also mechanisms that promote vascular repair. In this new field, characterization of endothelial progenitor cells has presented new opportunities for cardiovascular research. Summary Atherosclerosis begins in early life. Primary prevention strategies for adult cardiovascular disease beginning in childhood have great potential as the disease process is most reversible at this stage. Several guidelines have recently been published for screening and implementation of appropriate therapeutic choices in early life.