Abstracts

INTRODUCTION

Traditional cardiovascular risk factors and associated alterations can act for decades, even before the onset of clinical manifestations of cardiovascular events.¹¹11 McGill HC, McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence. Am J ClinNutr.2000:72(5Suppl):1307-15.^,2222 Stary HC. Natural history and histological classification of atherosclerotic lesions: an update. Arterioscler Thromb Vasc Biol.2000;20(5):1177-8. Arterial stiffness, an important determinant of blood pressure (BP) elevation and a predictor of adverse cardiovascular events,¹⁰10 Martyn CN, Greenwald SE. Impaired synthesis of elastin in walls of aorta and large conduit arteries during early development as an initiating event in pathogenesis of systemic hypertension. Lancet.1997;350(9082):953-5. DOI:10.1016/S0140-6736(96)10508-0
https://doi.org/10.1016/S0140-6736(96)10... ^,1717 Redington A, Sarkola EJT, Manlhiot C, Slorach C, Bradley TJ, Hui W, et al. Pressure changes evolution of the arterial structure and function from infancy to adolescence is related to anthropometric and blood pressure changes.Arterioscler Thromb Vasc Biol. 2012;32(10):2516-24. DOI:10.1161/ATVBAHA.112.252114
https://doi.org/10.1161/ATVBAHA.112.2521... can manifest as early as in childhood – in children with low levels of physical activity, type 1 diabetes, or obesity.³3 Celik A, Ozçetin M, Yerli Y, Damar IH, Kadı H, Koç F, et al. Increased aortic pulse wave velocity in obese children. Turk Kardiol Dern Ars. 2011:39(7):557-62. DOI:10.5543/tkda.2011.01694
https://doi.org/10.5543/tkda.2011.01694... ^,44 Donald AE, Charakida M, Falaschetti E, Lawlor D, Halcox J, Golding J, et al. Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur Heart J. 2010:31(12):1502-10. DOI:10.1093/eurheartj/ehq062
https://doi.org/10.1093/eurheartj/ehq062... ^,66 Haller H, Meier M. Diabetic nephropathy - current concepts in early diagnosis and treatment of diabetic microvascular complications.Herz. 2004;29(5):496-503.DOI:10.1007/s00059-004-2610-4
https://doi.org/10.1007/s00059-004-2610-...

The stiffness of the great arteries can be determined by various methods; the most indicated is measurement of pulse wave velocity (PWV), as it is easy to obtain and has good reproducibility.²⁴24 Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research. A scientific statement from the American Heart Association.Hypertension. 2009;54(5):919-50. DOI:10.1161/HYPERTENSIONAHA.109.192639
https://doi.org/10.1161/HYPERTENSIONAHA.... Carotid-femoral PWV has become the most widely used method for assessing the degree of stiffness of the great arteries.

Epidemiological studies have observed an increased incidence of hypertension in children, probably due to its association with overweight and physical inactivity.⁷7 Iampolsky MN, Souza FIS, Sarni RS. Influência do índice de massa corporal e da circunferência abdominal na pressão arterial sistêmica de crianças. Rev Paulista Ped. 2010;28(2):181-7. DOI:10.1590/S0103-05822010000200009
https://doi.org/10.1590/S0103-0582201000... ^,1313 Monego ET, Jardim PCBV. Determinantes de risco para doenças cardiovasculares em escolares. Arq Bras Cardiol.2006;87(1):37-45. DOI:10.1590/S0066-782x2006001400006
https://doi.org/10.1590/S0066-782x200600... Considering the association between arterial stiffness and hypertension, the evaluation of arterial stiffness in children²⁴24 Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research. A scientific statement from the American Heart Association.Hypertension. 2009;54(5):919-50. DOI:10.1161/HYPERTENSIONAHA.109.192639
https://doi.org/10.1161/HYPERTENSIONAHA.... can clarify this association at an early age. Age, sex, body mass index (BMI), and BP are important factors in determining arterial stiffness from childhood. Li et al⁸8 Li S, Chen W, Srinivasan SR, Berenson GS. Childhood blood pressure as a predictor of arterial stiffness in young adults: the Bogalusa heart study.Hypertension. 2004;43(3):541-6. DOI:10.1161/01HYP.0000115922.98155.23
https://doi.org/10.1161/01HYP.0000115922... (2004) and Donald et al⁴4 Donald AE, Charakida M, Falaschetti E, Lawlor D, Halcox J, Golding J, et al. Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur Heart J. 2010:31(12):1502-10. DOI:10.1093/eurheartj/ehq062
https://doi.org/10.1093/eurheartj/ehq062... (2010) stated that systolic BP (SBP) in childhood was positively associated with arterial stiffness. Donald et al⁴4 Donald AE, Charakida M, Falaschetti E, Lawlor D, Halcox J, Golding J, et al. Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur Heart J. 2010:31(12):1502-10. DOI:10.1093/eurheartj/ehq062
https://doi.org/10.1093/eurheartj/ehq062... (2010) and Aatola et al¹1 Aatola H, Hutri-Kähönen N, Juonala M, Viikarj JS, Hulkkonen J, Laitinen T, et al. Lifetime risk factors and arterial pulse wave velocity in adulthood: the cardiovascular risk in young Finns study.Hypertension. 2010;55(3):806-11. DOI:10.1161/HYPERTENSIONAHA.109.145102
https://doi.org/10.1161/HYPERTENSIONAHA.... (2010) observed that age was positively associated with PWV. According to Núñez et al¹1 Aatola H, Hutri-Kähönen N, Juonala M, Viikarj JS, Hulkkonen J, Laitinen T, et al. Lifetime risk factors and arterial pulse wave velocity in adulthood: the cardiovascular risk in young Finns study.Hypertension. 2010;55(3):806-11. DOI:10.1161/HYPERTENSIONAHA.109.145102
https://doi.org/10.1161/HYPERTENSIONAHA.... ⁴4 Donald AE, Charakida M, Falaschetti E, Lawlor D, Halcox J, Golding J, et al. Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur Heart J. 2010:31(12):1502-10. DOI:10.1093/eurheartj/ehq062
https://doi.org/10.1093/eurheartj/ehq062... (2010), obese children had higher PWV than their normal-weight peers. The same was observed in the study by Sakuragi et al¹⁹19 Sakuragi S, Abhayaratna K, Gravenmaker KJ, O’Reilly C, Srikusalanukul W, Budge MM, et al. Influence of adiposity and physical activity on arterial stiffness in healthy children:the lifestyle o four kids study.Hypertension. 2009;53(4):611-6. DOI:10.1161/HYPERTENSIONAHA.108.123364
https://doi.org/10.1161/HYPERTENSIONAHA.... (2009), where BMI and percentage of body fat were associated with higher carotid-femoral PWV levels in children and adolescents.

In recent years, special attention has been given to the assessment of these risk factors from a life cycle perspective. This approach was based on studies that evaluated the association of birth weight and the development of chronic diseases, confirmed by subsequent studies in different countries. This evidence led to the development of the hypothesis of fetal origins of disease, known as the Barker hypothesis,²2 Barker DJP. The origins of the developmental origins theory.J Inter Med. 2007;261(5):412-7. DOI:10.1111/j.1365-2796.2007.01809.x
https://doi.org/10.1111/j.1365-2796.2007... ^,1515 Osmond C, Barker DJP. Fetal, infant, and childhood growth are predictors of coronary heart disease, diabetes, and hypertension in adult men and women. Environ Health Perspect. 2000;108(Suppl 3):545-53. DOI:10.1289/ehp.00108s3545
https://doi.org/10.1289/ehp.00108s3545... which proposes that exposures during critical development periods (pregnancy and early childhood) may lead to permanent metabolic and/or structural changes to ensure the survival of the fetus in adverse conditions; however, these adaptations may increase the risk of developing chronic diseases in adulthood.

The relationship between low birth weight and arterial stiffness remains controversial, especially in low- and middle-income countries, as few studies have assessed this relationship in children from these regions; most studies were conducted in adults. Therefore, it is difficult to determine the exact moment at which the alterations found in the arteries were produced or whether these are typical of hypertension. Studies in children may contribute to a better understanding of this process in countries such as Brazil.

This study aimed to analyze the factors associated with stiffness of the great arteries in prepubertal children.

METHODS

This study had a convenience sample of 231 children aged 9-10 years enrolled in public and private schools in Vitória, ES, Southeastern Brazil, who had already participated in a previous study.⁵5 Faria CP, Nascimento L, Cade NV, Molina MCB. Prevalência de excesso de peso em crianças de 7 a 10 anos de Vitória-ES, Brasil: um estudo de base escolar. UFES. Rev Bras Pesq Saude.2011;13(1):31-7.

The sample size was calculated to reject the null hypothesis, with type I error of 5.0%, statistical power of 90.0%, and minimum difference in PWV of 0.5 m/s between groups. Consequently, the sample needed to comprise 224 children. Families were invited to participate in the study, considering the child’s prior participation in other studies. Data were collected from July 2010 to November 2011 at the Health Sciences Center of the Universidade Federal do Espírito Santo (UFES), using questionnaires and clinical examinations.

In the initial assessment, 250 children aged 9-10 years came to the Cardiovascular Research Clinic (CRC) to be examined. Of these, 19 were excluded for not undergoing the main tests involved in this study (PWV and BP). The sample consisted of 231 children, of whom 50.2% were girls and 55.4% were 10 years old.

The examinations were performed by trained researchers in a calm, quiet, and climate-controlled environment (22°C-24°C). The children made a scheduled visit to the CRC and fasted (10h-14h) before undergoing the blood tests; their BP was measured using the oscillometric method with an automatic device (OMROM^®HEM-705CP), and their PWV was measured. The children were seated in comfortable chairs, and chair height was adjusted so that their feet were flat on the floor. The measurements were made on the left arm, which was supported by a movable stand that maintained the brachial artery at heart level. Cuffs appropriately sized to fit the children’s arms were used; to choose the correct size, arm circumference was measured at the midpoint between the acromion and olecranon processes. The OMRON^® child cuff was used for subjects with arm circumference 16-22 cm and the OMRON^® adult cuff for subjects with arm circumference 23-33 cm. Three BP measurements were obtained, with a two-min interval between them. SBP, diastolic BP (DBP), and heart rate (HR) were determined by the arithmetic mean of the last two measurements. SBP and DBP were classified as normal (≤ 90^thpercentile for age and sex), borderline (90^th-95^th percentile) or high (≥ 95^th percentile), as recommended by the VI Brazilian Guidelines on Arterial Hypertension.²¹21 Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão; Sociedade Brasileira de Nefrologia. VI Diretrizes brasileiras de hipertensão. Arq Bras Cardiol. 2010;95(1Suppl 1):1-51. DOI:10.1590/S0066-782X2010001700001
https://doi.org/10.1590/S0066-782X201000... Later, they were re-categorized as normal BP (< 95^th percentile) or high BP (≥ 95^th percentile).

PWV was obtained after resting in the supine position for five minutes, and the subjects wore clothing that allowed easy access to the right femoral and carotid pulses. A tape measure was used to measure the distance between the sternal manubrium and the femoral pulse. PWV was measured by the simultaneous capture of pulse waves in the right carotid and femoral arteries. Dedicated software (Complior; Artech Medicale, France) assessed the adequacy of pulse waves; for positive cases, PWV was calculated by the ratio between the manubrium-femoral distance and the time delay between the two pulses. The PWV of every child was determined based on the mean, which was calculated automatically from 12 heartbeats at a regular HR. It was classified into tertiles based on the following cut-off points: tertile 1, < 5.1 m/s; tertile 2, 5.1-5.5 m/s; and tertile 3 > 5.5 m/s.

Anthropometric data were collected as recommended by the World Health Organization (WHO).²⁴24 Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research. A scientific statement from the American Heart Association.Hypertension. 2009;54(5):919-50. DOI:10.1161/HYPERTENSIONAHA.109.192639
https://doi.org/10.1161/HYPERTENSIONAHA.... Body weight was measured on an electronic scale (Toledo^®, model 2096; Brazil) with precision of 100 g. Height was measured by a portable stadiometer (Seca^®, model 206) attached to a flat wall with no baseboard.^aa World Health Organization. Indicators for assessing infant and young child feeding practices. Conclusions of consensus meeting held 6-8 November 2007 in Washington D.C., USA, 2007. Washington (DC); 2007. BMI was calculated, and the child was classified as normal weight or overweight according to WHO criteria. Waist circumference (WC) was measured using an anthropometric tape (Sanny^®) at the midpoint between the lower edge of the lowest rib and the iliac crest. The waist-to-height ratio (W/H) was obtained from the ratio of the waist and height measurements. The assessment of pubertal stage was performed using the criteria proposed by Tanner²³23 Tanner JM. Growth at adolescence. 2.ed. Oxford: Blackwell Scientific; 1962. (1962), and was reported by the children. Data on birth conditions, eating habits, and the child’s current health, as well as the durable consumer goods available at home were obtained through interviews with one of the parents or guardian.

Socioeconomic status was classified based on ownership of consumer goods and education level of the head of the household, as recommended by the Brazilian Association of Research Companies, and grouped into three categories:A+B, C, D+E.^bb Associação Brasileira de Empresas de Pesquisa. Critério de classificação econômica Brasil. São Paulo; 2011 [cited 2010 Oct 15]. Available from: http://www.abep.org/novo/Content.aspx?ContentID=139 This variable was only used for sample characterization.

Birth weight was recorded based on the information on the child’s health card. Approximately 30.0% of the cards did not include this data. In such cases, this was reported by the mother. Additionally, information on whether the delivery was preterm was collected.

The Kolmogorov-Smirnov test was used to assess the normality of continuous variables. Student’s t-test for independent samples and the Mann-Whitney test were used to compare the means of continuous variables with normal distribution and non-parametric variables, respectively. The Chi-squared test (X²) or Fisher’s exact test were used to compare proportions. One-way analysis of variance (ANOVA), followed by a Tukey test, were used to compare more than two means. The Kruskal-Wallis test was used for non-parametric variables. Pearson’s and Spearman’s correlation coefficients were used to test the correlations of the variables, according to their distribution. A multiple linear regression was used to identify the partial and total contribution of the factors in determining PWV values. To be included in the linear regression model, the variables with non-normal distribution were log-transformed. The residues of linear regression were evaluated for normality. The significance level was set at a < 0.05.

Statistical analyses were performed using SPSS for Windows, version 18.0.

This study was approved by the Research Ethics Committee of the Health Sciences Center of the Universidade Federal do Espírito Santo (Case 144/2010). The children’s participation was voluntary, and their families signed an informed consent form.

RESULTS

The main clinical characteristics of the participants were stratified according to the PWV tertile, with a mean of 5.3 m/s (standard deviation 0.52 m/s), minimum value of 4.1 m/s, and maximum of 7.8 m/s (Table 1). The only factor associated with PWV was nutritional status; 39.0% of the children classified in the highest PWV tertile were overweight, while this ratio was 33.0% (p = 0.01) in the lower tertiles.

Height was the only variable that was not associated with PWV (Table 2). Mean SBP and DBP increased from the first to the third PWV tertile (p < 0.01). The same occurred with the anthropometric variables WC, W/H, and body weight (p = 0.01; Table 2). The differences between tertiles were due almost exclusively to the increases in BP and in the variables related to the excess weight of the children in the third tertile, when compared with the first two.

Birth weight was not associated with PWV (p = 0.68). The higher the child’s BMI, the greater the PWV: 40.0% of the children with BMI > 20.3 kg/m² were in the highest PWV tertile (p = 0.01; Table 3).

Anthropometric variables and BP were significantly correlated with PWV (Table 4). However, due to colinearity between some of the anthropometric variables tested, only BMI and W/H were included in the multiple regression model. The other variables in the model were SBP, DBP, and sex.

Residual analysis demonstrated homoscedasticity. The factors that explained the changes in PWV were BMI and DBP (p < 0.01; Table 5).

DISCUSSION

BMI was associated with PWV in children aged 9-10 years. Although other anthropometric variables were also associated, only BMI remained in the final regression model. This finding is similar to that of Sakuragi et al¹⁹19 Sakuragi S, Abhayaratna K, Gravenmaker KJ, O’Reilly C, Srikusalanukul W, Budge MM, et al. Influence of adiposity and physical activity on arterial stiffness in healthy children:the lifestyle o four kids study.Hypertension. 2009;53(4):611-6. DOI:10.1161/HYPERTENSIONAHA.108.123364
https://doi.org/10.1161/HYPERTENSIONAHA.... (2009), Núñez et al¹⁴14 Núñez F, Martínez-Costa C, Sánchez-Zahonero J, Morata J, Chorro FJ, Brines J. Medida de la rigidez de la arteria carótida como marcador precoz de lesión vascular en ni-os y adolescentes con factores de riesgo cardiovascular.Rev Esp Cardiol. 2010;63(11):1253-60. DOI:10.1016/S0300-8932(10)70295-5
https://doi.org/10.1016/S0300-8932(10)70... (2010), and Celik et al³3 Celik A, Ozçetin M, Yerli Y, Damar IH, Kadı H, Koç F, et al. Increased aortic pulse wave velocity in obese children. Turk Kardiol Dern Ars. 2011:39(7):557-62. DOI:10.5543/tkda.2011.01694
https://doi.org/10.5543/tkda.2011.01694... (2011), in which a positive association was observed between overweight and arterial stiffness in children and adolescents. Although obesity is an important risk factor for cardiovascular disease, the pathophysiological mechanisms that associate it with arterial stiffness are not fully understood,¹⁸18 Safar ME, Czemichov S, Blacher J. Obesity, arterial stiffness, and cardiovascular risk. J Am Soc Nephrol.2006;17(4):109-11.especially in the age group assessed in the present study.

Unlike other studies, no significant association was observed between birth weight and PWV. The relationship between birth weight and arterial stiffness remains controversial. Martin et al⁹9 Martin H, Hu J, Gennser G, Norman M. Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight.Circulation. 2000;102(22):2739-44. DOI:10.1161/01.CIR.102.22.2739
https://doi.org/10.1161/01.CIR.102.22.27... (2000) found a negative correlation between birth weight and carotid artery stiffness, assessed by ultrasound. Miles et al¹²12 Miles KL, McDonnell BJ, Maki-Petaja KM, Yasmin CJR, Wilkinson IB, McEniery CM. Enigma Study investigators. The impact of birth weight on blood pressure and arterial stiffness in later life: the enigma study. J Hypertens. 2011;29(12):2324-31. DOI:10.1097/HJH.0b013e32834d0ca1
https://doi.org/10.1097/HJH.0b013e32834d... (2011) found no association between arterial stiffness and birth weight, as assessed by carotid-femoral PWV. Conversely, in the assessment of carotid-femoral PWV in adolescents, Salvi et al²⁰20 Salvi P, Revera M, Joly L, Reusz G, Iaia M, Benkhedda S, et al. Role of birth weigth and postnaltal growth on pulse wave velocity in teenagers.J Adolesc Health. 2012;51(4):373-9. DOI:10.1016/j.jadohealth.2012.01.009
https://doi.org/10.1016/j.jadohealth.201... (2012) found a negative association between low birth weight and PWV. However, birth data was obtained directly from clinical records, thus reducing the chance of recall bias.

Studies assessing arterial stiffness in children are controversial. This is mainly due to the divergent methodologies used to measure arterial stiffness, such as different devices and arterial segments assessed. The distribution of blood components varies depending on the location of the vessel. The central arteries have a higher degree of elasticity because of high elastin/collagen ratio and low influence of smooth muscle tone. In contrast, the peripheral vessels have less elasticity, as they have a lower elastin/collagen ratio. Thus, the measurement method and the arterial segment evaluated must be considered. The results will probably not be the same if measurements are done in different segments. The values obtained in the aortic-brachial segment will be higher than those obtained in the carotid-femoral, considering the amount of elastin in each segment.²⁴24 Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research. A scientific statement from the American Heart Association.Hypertension. 2009;54(5):919-50. DOI:10.1161/HYPERTENSIONAHA.109.192639
https://doi.org/10.1161/HYPERTENSIONAHA.... This study used the carotid-femoral PWV because it is considered to be the best method for assessing stiffness of the great arteries, especially the aorta.

The high frequency of overweight was probably related to the sample selection strategy. The participants had already participated in previous studies. Therefore, it is possible that parents who were more concerned with their child’s weight responded more favorably to the invitation to participate in this study. This bias, however, does not hinder the objectives of this study, which did not aim to estimate the prevalence of structural or functional alterations in children, but rather to associate these variables with an outcome that characterizes stiffness of the great arteries, the carotid-femoral PWV.

Another limitation of this study is its cross-sectional design, which is not suitable for inferring causal association. Cohort studies provide the best conditions for assessing findings.²⁰20 Salvi P, Revera M, Joly L, Reusz G, Iaia M, Benkhedda S, et al. Role of birth weigth and postnaltal growth on pulse wave velocity in teenagers.J Adolesc Health. 2012;51(4):373-9. DOI:10.1016/j.jadohealth.2012.01.009
https://doi.org/10.1016/j.jadohealth.201... ^,2626 Yu ZB, Han SP, Zhu GZ, Zhu C, Wang XJ, Cao XG, et al. Birth weight and subsequent risk of obesity: a systematic review and meta-analysis.Obes Rev. 2011;12(7):525-42. DOI:10.1111/j.1467-789X.2011.00867.x
https://doi.org/10.1111/j.1467-789X.2011... However, the measurements were checked for quality control and the appropriate methodology was used for establishing the associations found in this study.

This is one of the first studies in Brazil to assess arterial stiffness measured by carotid-femoral PWV in prepubertal children. The results of the present study can contribute to a better understanding of this subject in different locations where the lifestyle differs from that of the countries in which these parameters are usually studied. Arterial stiffness is often measured in adults, but its use in children has been previously reported. Most studies have demonstrated an association between increased PWV, age, and BP.¹⁶16 Pizzi OL, Brandão AA, Pozzan R, Magalhães MEC, Campana EMG, Fonseca FL, et al. Velocidade da onda de pulso, pressão arterial e adipocitocinas em adultos jovens: estudo do Rio de Janeiro. Arq Bras Cardiol.2013;100(1):60-6. DOI:10.1590/S0066-782x2012005000116 In this study, BP was controlled in the linear regression adjustment to assess PWV, and the age range studied was narrow (9-10 years). Thus, it did not affect the PWV result of in the studied population or the other findings.

Although BP was measured three times under controlled environmental conditions by a trained professional, this measurement cannot be considered as a reflection of the BP of the assessed children. Ideally, measurements are carried out at different times. Nonetheless, children who were in puberty were excluded, thus avoiding potential hormonal effects on the outcome (PWV) and on related factors such as overweight.

Overweight was the most important factor in determining arterial stiffness in this sample. Although it has not been widely studied in Brazil, the evaluation of the vascular structure and function measured by PWV can be useful for the identification of early vascular involvement in children. Therefore, the contribution of this research on the discussion of children’s health is timely, particularly regarding the identification of future cardiovascular problems.

REFERENCES

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