Atherosclerosis 233 (2014) 370e374
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Weight gain in infancy is associated with carotid extra-medial thickness in later childhood Michael R. Skilton a, *, Tim R. Sullivan b, Julian G. Ayer c, d, Frances L. Garden d, e, f, Jason A. Harmer d, Stephen R. Leeder d, f, g, Brett G. Toelle e, Karen Webb h, Guy B. Marks e, David S. Celermajer b, d a
Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia The Heart Centre for Children, The Children’s Hospital at Westmead, Australia d Sydney Medical School, University of Sydney, Australia e Woolcock Institute of Medical Research, Australia f Sydney School of Public Health, University of Sydney, Australia g Menzies Centre for Health Policy, University of Sydney, Sydney, Australia h Atkins Center for Weight and Health, Department of Nutritional Sciences and Toxicology and School of Public Health, University of California, Berkeley, CA, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 August 2013 Received in revised form 7 January 2014 Accepted 10 January 2014 Available online 24 January 2014
Objective: Early life is an important period for determining future risk of cardiovascular disease. Carotid extra-medial thickness is a novel noninvasive measure that estimates arterial adventitial thickness, information concerning vascular health not captured by assessment of arterial intima-media thickness alone. We sought to determine whether fetal growth and early postnatal growth are associated with carotid extra-medial thickness in 8 year old children. Methods: Carotid extra-medial thickness was assessed by high-resolution ultrasound in 379 non-diabetic children aged 8-years, with complete data for birth weight, gestational age, early postnatal weight gain and carotid extra-medial thickness. Results: Weight gain during infancy, from birth to 18 months of age, was significantly and positively associated with carotid EMT (11 mm per kg length-adjusted weight gain [95% CI 3, 18], P ¼ 0.007). This association was significantly stronger in boys than girls (Pheterogeneity ¼ 0.005). By contrast, there was no significant association between birth weight and carotid EMT (6 mm/kg birth weight [95% CI 12, 24], P ¼ 0.51). Conclusion: Excessive weight gain during infancy is associated with increased carotid extra-medial thickness, indicating that the alterations to the vasculature associated with excessive early postnatal growth likely include arterial adventitial thickening. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Fetal growth Obesity Adventitia Risk factors Imaging Childhood
1. Introduction Early life is an important period for determining future risk of cardiovascular disease. For example, there is a large and consistent body of evidence indicating that birth weight, as a proxy for fetal growth, is inversely associated with risk of adult cardiovascular disease [1,2]. Arterial intima-media thickness (IMT), a noninvasive measure of subclinical atherosclerosis, can be assessed in childhood * Corresponding author. Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. Tel.: þ61 2 95153383; fax: þ61 2 95506262. E-mail address: [email protected] (M.R. Skilton). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.020
and appears to be a useful tool to identify potential early life risk factors [3,4]. Indeed, we have demonstrated that those born with impaired fetal growth have increased arterial IMT, from infancy through adulthood [5e7]. Another potentially important period of early growth is during infancy. Early weight gain is associated with increased risk of overweight and obesity later in childhood [8,9], and consequently with obesity-related cardiovascular risk factors including systemic inflammation and blood pressure [9]. Furthermore, early weight gain is associated with higher arterial IMT in later childhood, independent of adiposity [9], suggesting that excessive weight gain during this critical period of development may influence the risk of cardiovascular disease.
M.R. Skilton et al. / Atherosclerosis 233 (2014) 370e374
In addition to the arterial intima and media, there is experimental evidence that atherosclerosis also involves structural alterations to the arterial adventitia [10e13], and that paracrine signaling of adventitial origin can affect medial structure [14]. Accordingly, assessment of arterial adventitial structure may provide information concerning arterial health that is not captured by assessment of arterial IMT alone [15]. We have recently developed a novel technique, carotid extra-medial thickness (EMT), which allows for noninvasive assessment of arterial adventitial thickness [15,16]. It is not known whether or not early life risk factors, specifically fetal and infant growth, are associated with adventitial thickness in later life. Accordingly, we sought to describe whether or not fetal growth and early postnatal growth are associated with carotid EMT in 8 year old children followed since birth in a longitudinal study.
371
Additional consent was obtained from 305 of these participants (80%) to obtain a non-fasting blood sample at age 8 years. Total cholesterol and high-density lipoprotein cholesterol (HDL-c) were measured by standard enzymatic procedures, and high-sensitivity C-reactive protein (hsCRP) measured by an immunoturbidometric method (Roche Diagnostics, Australia). Non-HDL-c was calculated as total cholesterol minus HDL-c. Systolic blood pressure and diastolic blood pressure were measured at the brachial arterial with a validated oscillometric device and appropriate sized cuff (Welch Allyn Vital Signs Monitor, NY), after a 10 min rest with the participant lying supine. The average of two measures taken 10 min apart was used for analysis. A third measure was obtained if the first two measures differed by more than 10 mm Hg. 2.3. Carotid EMT & carotid IMT
2. Methods 2.1. Participants This study reports results from 379 non-diabetic children enrolled before birth (between September 1997 and December 1999) in the Childhood Asthma Prevention Study (CAPS). CAPS was a randomized controlled trial to determine whether dietary omega3 supplementation and/or house dust mite reduction may reduce the incidence of atopy and/or asthma in children with at least one parent or sibling with diagnosis or symptoms of asthma [17]. Exclusion criteria included infants from a multiple birth pregnancy, and those born before 36 weeks gestation. In this trial, participants were studied at birth (n ¼ 616), 18 months (n ¼ 554), 3 years, and 5 years of age (n ¼ 516) [18]. They were subsequently followed up at age 8 years (n ¼ 450) as part of an ongoing longitudinal cohort consisting of the original randomized trial participants. A cardiovascular substudy, CardioCAPS, was undertaken at 8 years. 405 non-diabetic CAPS study subjects participated in CardioCAPS. These participants had similar characteristics at baseline to those in the original CAPS trial, with the exception of higher maternal age and education [19]. Their anthropometric and cardiovascular risk characteristics were comparable to those of an unselected community-based population of similar age from the same region [20,21]. Trial interventions did not alter vascular risk factors or anthropometric measures in these children [19]. The digital version of one participant’s ultrasound scan was missing, leaving 404 participants with available scans. Carotid EMT was measureable in either the left or right common carotid artery in 389 of 404 participants (96%) [22]. The current study reports results from those 379 non-diabetic children followed to age 8 years who had complete data for birth weight, gestational age, early postnatal weight gain and carotid EMT. This study was approved by the human research ethics committees of the University of Sydney, The Children’s Hospital at Westmead, and Sydney South West Area Health Service. The parent or legal guardian of each participating child provided written informed consent before taking part. 2.2. Anthropometry and cardiovascular risk factors Birth weight and length were recorded from hospital records. Subsequent anthropometric measures were assessed at each study visit. Weight was measured to the nearest 0.1 kg using calibrated electronic scales; recumbent length was measured to the nearest 0.5 cm from birth to 2 years and standing height was measured at each visit from 2 years to the nearest 0.5 cm using a stadiometer. Body mass index (BMI) z-score at age 8 years was calculated from US growth charts from the Centers for Disease Control and Prevention [23].
The protocol used in this study for the acquisition of carotid IMT recommended the use of the jugular vein as a sonographic window, allowing technically satisfactory analysis of carotid EMT in 96% of participants. Carotid EMT was assessed by a single experienced EMT reader (M.R.S.), blinded to all clinical characteristics, as previously described [15]. Briefly, the distance from the carotid mediaadventitia interface to the jugular intimaelumen interface was measured using semi-automated software (M’ATH SR version 2.0, Metris, France), along a 0.3e1.0 cm long segment w1.0e1.5 cm proximal to the carotid bulb, at end-diastole from two cardiac cycles. The average of the two measures was used. We have previously demonstrated this technique to be highly reproducible [15,22]. Carotid IMT was measured 0e1 cm proximal to the carotid bulb, at end-diastole, from three cardiac cycles in both the left and right carotid arteries, as previously described [19,24]. 2.4. Statistical analysis Our pre-specified primary endpoint was the association between early life weight gain and carotid EMT. A further prespecified subgroup analysis was to examine this relationship separately, in boys and girls. This is because we have previously found evidence of sex-specific associations of cardiovascular risk factors with carotid EMT in childhood [22]. Also, we have demonstrated that carotid EMT differs between the right and left carotid arteries, with the right carotid EMT being slightly greater [15,22]. Carotid EMT was therefore adjusted for side of measurement (left only, right only, or both) accordingly. Similar results were found for maximum carotid EMT, and as such only results for mean carotid EMT are shown. Heterogeneity by sex was assessed as previously described [25]. Fetal growth was estimated from birth weight, adjusting for gestational age [5]. Early postnatal growth was calculated as the residual of change in weight from birth to 18 months on the concurrent change in length from birth to 18 months. This lengthadjusted weight gain reflects weight gain above or below that expected given stature growth. Associations of fetal growth and early postnatal growth with carotid EMT were determined by multivariable linear regression. All models were adjusted for age at 8 year visit, randomization group, maternal education, and sex (except in sex-stratified analyses). Further models detailing the association of early postnatal growth with carotid EMT were adjusted for: carotid IMT, to determine associations that are independent of the gold standard noninvasive measure of subclinical atherosclerosis; height, a strong predictor of carotid EMT in children; body size at birth, a strong determinant of later cardiovascular risk; cardiovascular risk factors at age 8 years, to demonstrate independence from established
372
M.R. Skilton et al. / Atherosclerosis 233 (2014) 370e374
cardiovascular risk factors; and predictors of early postnatal growth, in an attempt to determine whether associations are for growth per se, or may be a surrogate for other early life risk factors. There was no evidence of problematic multicollinearity in these models, with all variables having variable inflation factors
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Weight gain in infancy is associated with carotid extra-medial thickness in later childhood Michael R. Skilton a, *, Tim R. Sullivan b, Julian G. Ayer c, d, Frances L. Garden d, e, f, Jason A. Harmer d, Stephen R. Leeder d, f, g, Brett G. Toelle e, Karen Webb h, Guy B. Marks e, David S. Celermajer b, d a
Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Australia Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia The Heart Centre for Children, The Children’s Hospital at Westmead, Australia d Sydney Medical School, University of Sydney, Australia e Woolcock Institute of Medical Research, Australia f Sydney School of Public Health, University of Sydney, Australia g Menzies Centre for Health Policy, University of Sydney, Sydney, Australia h Atkins Center for Weight and Health, Department of Nutritional Sciences and Toxicology and School of Public Health, University of California, Berkeley, CA, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 August 2013 Received in revised form 7 January 2014 Accepted 10 January 2014 Available online 24 January 2014
Objective: Early life is an important period for determining future risk of cardiovascular disease. Carotid extra-medial thickness is a novel noninvasive measure that estimates arterial adventitial thickness, information concerning vascular health not captured by assessment of arterial intima-media thickness alone. We sought to determine whether fetal growth and early postnatal growth are associated with carotid extra-medial thickness in 8 year old children. Methods: Carotid extra-medial thickness was assessed by high-resolution ultrasound in 379 non-diabetic children aged 8-years, with complete data for birth weight, gestational age, early postnatal weight gain and carotid extra-medial thickness. Results: Weight gain during infancy, from birth to 18 months of age, was significantly and positively associated with carotid EMT (11 mm per kg length-adjusted weight gain [95% CI 3, 18], P ¼ 0.007). This association was significantly stronger in boys than girls (Pheterogeneity ¼ 0.005). By contrast, there was no significant association between birth weight and carotid EMT (6 mm/kg birth weight [95% CI 12, 24], P ¼ 0.51). Conclusion: Excessive weight gain during infancy is associated with increased carotid extra-medial thickness, indicating that the alterations to the vasculature associated with excessive early postnatal growth likely include arterial adventitial thickening. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Fetal growth Obesity Adventitia Risk factors Imaging Childhood
1. Introduction Early life is an important period for determining future risk of cardiovascular disease. For example, there is a large and consistent body of evidence indicating that birth weight, as a proxy for fetal growth, is inversely associated with risk of adult cardiovascular disease [1,2]. Arterial intima-media thickness (IMT), a noninvasive measure of subclinical atherosclerosis, can be assessed in childhood * Corresponding author. Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia. Tel.: þ61 2 95153383; fax: þ61 2 95506262. E-mail address: [email protected] (M.R. Skilton). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.020
and appears to be a useful tool to identify potential early life risk factors [3,4]. Indeed, we have demonstrated that those born with impaired fetal growth have increased arterial IMT, from infancy through adulthood [5e7]. Another potentially important period of early growth is during infancy. Early weight gain is associated with increased risk of overweight and obesity later in childhood [8,9], and consequently with obesity-related cardiovascular risk factors including systemic inflammation and blood pressure [9]. Furthermore, early weight gain is associated with higher arterial IMT in later childhood, independent of adiposity [9], suggesting that excessive weight gain during this critical period of development may influence the risk of cardiovascular disease.
M.R. Skilton et al. / Atherosclerosis 233 (2014) 370e374
In addition to the arterial intima and media, there is experimental evidence that atherosclerosis also involves structural alterations to the arterial adventitia [10e13], and that paracrine signaling of adventitial origin can affect medial structure [14]. Accordingly, assessment of arterial adventitial structure may provide information concerning arterial health that is not captured by assessment of arterial IMT alone [15]. We have recently developed a novel technique, carotid extra-medial thickness (EMT), which allows for noninvasive assessment of arterial adventitial thickness [15,16]. It is not known whether or not early life risk factors, specifically fetal and infant growth, are associated with adventitial thickness in later life. Accordingly, we sought to describe whether or not fetal growth and early postnatal growth are associated with carotid EMT in 8 year old children followed since birth in a longitudinal study.
371
Additional consent was obtained from 305 of these participants (80%) to obtain a non-fasting blood sample at age 8 years. Total cholesterol and high-density lipoprotein cholesterol (HDL-c) were measured by standard enzymatic procedures, and high-sensitivity C-reactive protein (hsCRP) measured by an immunoturbidometric method (Roche Diagnostics, Australia). Non-HDL-c was calculated as total cholesterol minus HDL-c. Systolic blood pressure and diastolic blood pressure were measured at the brachial arterial with a validated oscillometric device and appropriate sized cuff (Welch Allyn Vital Signs Monitor, NY), after a 10 min rest with the participant lying supine. The average of two measures taken 10 min apart was used for analysis. A third measure was obtained if the first two measures differed by more than 10 mm Hg. 2.3. Carotid EMT & carotid IMT
2. Methods 2.1. Participants This study reports results from 379 non-diabetic children enrolled before birth (between September 1997 and December 1999) in the Childhood Asthma Prevention Study (CAPS). CAPS was a randomized controlled trial to determine whether dietary omega3 supplementation and/or house dust mite reduction may reduce the incidence of atopy and/or asthma in children with at least one parent or sibling with diagnosis or symptoms of asthma [17]. Exclusion criteria included infants from a multiple birth pregnancy, and those born before 36 weeks gestation. In this trial, participants were studied at birth (n ¼ 616), 18 months (n ¼ 554), 3 years, and 5 years of age (n ¼ 516) [18]. They were subsequently followed up at age 8 years (n ¼ 450) as part of an ongoing longitudinal cohort consisting of the original randomized trial participants. A cardiovascular substudy, CardioCAPS, was undertaken at 8 years. 405 non-diabetic CAPS study subjects participated in CardioCAPS. These participants had similar characteristics at baseline to those in the original CAPS trial, with the exception of higher maternal age and education [19]. Their anthropometric and cardiovascular risk characteristics were comparable to those of an unselected community-based population of similar age from the same region [20,21]. Trial interventions did not alter vascular risk factors or anthropometric measures in these children [19]. The digital version of one participant’s ultrasound scan was missing, leaving 404 participants with available scans. Carotid EMT was measureable in either the left or right common carotid artery in 389 of 404 participants (96%) [22]. The current study reports results from those 379 non-diabetic children followed to age 8 years who had complete data for birth weight, gestational age, early postnatal weight gain and carotid EMT. This study was approved by the human research ethics committees of the University of Sydney, The Children’s Hospital at Westmead, and Sydney South West Area Health Service. The parent or legal guardian of each participating child provided written informed consent before taking part. 2.2. Anthropometry and cardiovascular risk factors Birth weight and length were recorded from hospital records. Subsequent anthropometric measures were assessed at each study visit. Weight was measured to the nearest 0.1 kg using calibrated electronic scales; recumbent length was measured to the nearest 0.5 cm from birth to 2 years and standing height was measured at each visit from 2 years to the nearest 0.5 cm using a stadiometer. Body mass index (BMI) z-score at age 8 years was calculated from US growth charts from the Centers for Disease Control and Prevention [23].
The protocol used in this study for the acquisition of carotid IMT recommended the use of the jugular vein as a sonographic window, allowing technically satisfactory analysis of carotid EMT in 96% of participants. Carotid EMT was assessed by a single experienced EMT reader (M.R.S.), blinded to all clinical characteristics, as previously described [15]. Briefly, the distance from the carotid mediaadventitia interface to the jugular intimaelumen interface was measured using semi-automated software (M’ATH SR version 2.0, Metris, France), along a 0.3e1.0 cm long segment w1.0e1.5 cm proximal to the carotid bulb, at end-diastole from two cardiac cycles. The average of the two measures was used. We have previously demonstrated this technique to be highly reproducible [15,22]. Carotid IMT was measured 0e1 cm proximal to the carotid bulb, at end-diastole, from three cardiac cycles in both the left and right carotid arteries, as previously described [19,24]. 2.4. Statistical analysis Our pre-specified primary endpoint was the association between early life weight gain and carotid EMT. A further prespecified subgroup analysis was to examine this relationship separately, in boys and girls. This is because we have previously found evidence of sex-specific associations of cardiovascular risk factors with carotid EMT in childhood [22]. Also, we have demonstrated that carotid EMT differs between the right and left carotid arteries, with the right carotid EMT being slightly greater [15,22]. Carotid EMT was therefore adjusted for side of measurement (left only, right only, or both) accordingly. Similar results were found for maximum carotid EMT, and as such only results for mean carotid EMT are shown. Heterogeneity by sex was assessed as previously described [25]. Fetal growth was estimated from birth weight, adjusting for gestational age [5]. Early postnatal growth was calculated as the residual of change in weight from birth to 18 months on the concurrent change in length from birth to 18 months. This lengthadjusted weight gain reflects weight gain above or below that expected given stature growth. Associations of fetal growth and early postnatal growth with carotid EMT were determined by multivariable linear regression. All models were adjusted for age at 8 year visit, randomization group, maternal education, and sex (except in sex-stratified analyses). Further models detailing the association of early postnatal growth with carotid EMT were adjusted for: carotid IMT, to determine associations that are independent of the gold standard noninvasive measure of subclinical atherosclerosis; height, a strong predictor of carotid EMT in children; body size at birth, a strong determinant of later cardiovascular risk; cardiovascular risk factors at age 8 years, to demonstrate independence from established
372
M.R. Skilton et al. / Atherosclerosis 233 (2014) 370e374
cardiovascular risk factors; and predictors of early postnatal growth, in an attempt to determine whether associations are for growth per se, or may be a surrogate for other early life risk factors. There was no evidence of problematic multicollinearity in these models, with all variables having variable inflation factors
