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Reproducibility of aortic intima-media thickness in infants using edge-detection software and manual caliper measurements

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      Abstract

      Background

      Aortic intima-media thickness measured by transabdominal ultrasound (aIMT) is an intermediate phenotype of cardiovascular risk. We aimed to (1) investigate the reproducibility of aIMT in a population-derived cohort of infants; (2) establish the distribution of aIMT in early infancy; (3) compare measurement by edge-detection software to that by manual sonographic calipers; and (4) assess the effect of individual and environmental variables on image quality.

      Methods

      Participants were term infants recruited to a population-derived birth cohort study. Transabdominal ultrasound was performed at six weeks of age by one of two trained operators. Thirty participants had ultrasounds performed by both operators on the same day. Data were collected on environmental (infant sleeping, presence of a sibling, use of sucrose, timing during study visit) and individual (post-conception age, weight, gender) variables. Two readers assessed image quality and measured aIMT by edge-detection software and a subset by manual sonographic calipers. Measurements were repeated by the same reader and between readers to obtain intra-observer and inter-observer reliability.

      Results

      Aortic IMT was measured successfully using edge-detection in 814 infants, and 290 of these infants also had aIMT measured using manual sonographic calipers. The intra-reader intra-class correlation (ICC) (n = 20) was 0.90 (95% CI 0.76, 0.96), mean difference 1.5 μm (95% LOA −39, 59). The between reader ICC using edge-detection (n = 20) was 0.92 (95% CI 0.82, 0.97) mean difference 2 μm (95% LOA −45.0, 49.0) and with manual caliper measurement (n = 290) the ICC was 0.84 (95% CI 0.80, 0.87) mean difference 5 μm (95% LOA −51.8, 61.8). Edge-detection measurements were greater than those from manual sonographic calipers (mean aIMT 618 μm (50) versus mean aIMT 563 μm (49) respectively; p < 0.001, mean difference 44 μm, 95% LOA −54, 142). With the exception of infant crying (p = 0.001), no associations were observed between individual and environmental variables and image quality.

      Conclusion

      In a population-derived cohort of term infants, aIMT measurement has a high level of intra and inter-reader reproducibility. Measurement of aIMT using edge-detection software gives higher inter-reader ICC than manual sonographic calipers. Image quality is not substantially affected by individual and environmental factors.

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      Most cited references 23

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      Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association.

      Deterioration in endothelial function and arterial stiffness are early events in the development of cardiovascular diseases. In adults, noninvasive measures of atherosclerosis have become established as valid and reliable tools for refining cardiovascular risk to target individuals who need early intervention. With limited pediatric data, the use of these techniques in children and adolescents largely has been reserved for research purposes. Therefore, this scientific statement was written to (1) review the current literature on the noninvasive assessment of atherosclerosis in children and adolescents, (2) make recommendations for the standardization of these tools for research, and (3) stimulate further research with a goal of developing valid and reliable techniques with normative data for noninvasive clinical evaluation of atherosclerosis in pediatric patients. Precise and reliable noninvasive tests for atherosclerosis in youth will improve our ability to estimate future risk for heart attack and stroke. Currently, large longitudinal studies of cardiovascular risk factors in youth, such as the Bogalusa and Muscatine studies, lack sufficient adult subjects experiencing hard outcomes, such as heart attack and stroke, to produce meaningful risk scores like those developed from Framingham data.
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        Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

        To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2+/-1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P < 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651+/-87,449 and 451,255+/-37,448 micron2 per section, respectively; mean+/-SD) than aortas from normocholesterolemic mothers (61,862+/-9,555 micron2; P < 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde- and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and OxLDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo.
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          Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children.

          Autopsy studies in children have shown that atherosclerotic lesions begin to develop first in the intima of the aorta. Recent developments in ultrasound techniques have made it possible to visualize the intima-medial thickness of the abdominal aorta directly (aIMT). Therefore, we examined the feasibility of measuring aIMT in children and studied its value in distinguishing high-risk children from healthy controls compared with a more established marker of subclinical atherosclerosis, the common carotid artery intima-medial thickness (cIMT). IMTs were measured using high-resolution (13 MHz) ultrasound in 88 children (aged 11+/-2 years); 16 had hypercholesterolemia (LDL cholesterol, 5.1+/-1.2 mmol/L), 44 had type 1 diabetes (mean duration, 4.4+/-3.1 years; LDL cholesterol, 2.3+/-0.7 mmol/L), and 28 were healthy (controls; LDL cholesterol, 2.5+/-0.8 mmol/L). High-risk children had significantly increased aIMTs and cIMTs (both P<0.001) compared with controls. In controls, aIMT was similar to cIMT (P=NS), but aIMT was higher than cIMT in the children with hypercholesterolemia and diabetes (both P<0.01). Both markers showed excellent and approximately equal between-observer (<4%) and between-subject variation (<5%). Children with hypercholesterolemia and diabetes show increased IMTs compared with healthy controls, with a relatively greater increase in the aIMT than in the cIMT. Because atherosclerosis begins first in the intima of the aorta, these data suggest that the aIMT might provide the best currently available noninvasive marker of preclinical atherosclerosis in children.
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            Author and article information

            Affiliations
            [1]Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Australia
            [2]Child Health Research Unit, Barwon Health, Geelong, Australia
            [3]University of Melbourne, Parkville, Australia
            [4]Deakin University, Burwood, Australia
            [5]Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Sydney, Australia
            Author notes
            on behalf of the Barwon Infant Study investigator group
            Contributors
            Journal
            Cardiovasc Ultrasound
            Cardiovasc Ultrasound
            Cardiovascular Ultrasound
            BioMed Central
            1476-7120
            2014
            3 June 2014
            : 12
            : 18
            24894574
            4061507
            1476-7120-12-18
            10.1186/1476-7120-12-18
            Copyright © 2014 McCloskey et al.; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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