Assessment of Intima-Media Thickness in Healthy Children Aged 1 to 15 Years

Abstract

Background:

Carotid intima-media thickness (CIMT) has been shown to be increased in children and adolescents with traditional cardiovascular risk factors such as obesity, hypertension, and chronic kidney disease, compared with those of healthy children.

Objective:

To assess the influence of sex, age and body mass index (BMI) on the CIMT in healthy children and adolescents aged 1 to 15 years.

Methods:

A total of 280 healthy children and adolescents (males, n=175; mean age, 7.49±3.57 years; mean BMI, 17.94±4.1 kg/m²) were screened for CIMT assessment. They were divided into 3 groups according to age: GI, 1 to 5 years [n=93 (33.2%); males, 57; mean BMI, 16±3 kg/m²]; GII, 6 to 10 years [n=127 (45.4%); males, 78; mean BMI, 17.9±3.7 kg/m²], and GIII, 11 to 15 years [n=60 (21.4%); males, 40; mean BMI, 20.9±4.5 kg/m²].

Results:

There was no significant difference in CIMT values between male and female children and adolescents (0.43±0.06 mm vs. 0.42±0.05 mm, respectively; p=0.243). CIMT correlated with BMI neither in the total population nor in the 3 age groups according to Pearson correlation coefficient. Subjects aged 11 to 15 years had the highest CIMT values (GI vs. GII, p=0.615; GI vs. GIII, p=0.02; GII vs. GIII, p=0.004).

Conclusions:

CIMT is constant in healthy children younger than 10 years, regardless of sex or BMI. CIMT increases after the age of 10 years.

Keywords:
Child; Carotid Artery; Carotid Intima-Media Thickness; Atherosclerosis; Ultrasonography

Resumo

Fundamentos:

A espessura médio-intimal (EMI) na artéria carótida comum tem se mostrado aumentada em crianças e adolescentes com fatores de risco tradicionais, como obesidade, hipertensão e doença renal crônica, quando comparada à de crianças saudáveis.

Objetivos:

Avaliar a influência do sexo, idade e índice de massa corpórea (IMC) sobre a EMI em crianças e adolescentes saudáveis entre 1 e 15 anos de idade.

Métodos:

Este estudo incluiu 280 indivíduos saudáveis (sexo masculino, n=175; idade, 7,49±3,57 anos; IMC, 17,94±4,1 kg/m²), que foram divididos em 3 grupos de acordo com a faixa etária: GI, crianças de 1 a 5 anos [n=93 (33,2%); sexo masculino, 57; IMC, 16±3 kg/m²]; GII, crianças de 6 a 10 anos [n=127 (45,4%); sexo masculino, 78; IMC, 17,9±3,7 kg/m²]; e GIII, crianças de 11 a 15 anos [n=60 (21,4%); sexo masculino, 40; IMC, 20,9±4,5 kg/m²].

Resultados:

Não houve diferença significativa nos valores da EMI entre os sexos (masculino, 0,43±0,06 mm; feminino, 0,42±0.05 mm; p=0,243). A EMI não se correlacionou com o IMC na população total ou nos 3 grupos de acordo com o coeficiente de correlação de Pearson. Crianças entre 11 e 15 anos apresentaram maiores valores de EMI (GI vs. GII, p=0,615; GI vs. GIII, p=0,02; GII vs. GIII, p=0,004).

Conclusões:

Independentemente de sexo e IMC, a EMI é constante em crianças saudáveis abaixo dos 10 anos de idade, aumentando a partir daí.

Palavras-chave:
Crianças; Artéria Carótida; Espessura Íntima-Média Carotídea; Aterosclerose; Ultrassonografia

Introduction

In 1986 Pignoli et al.¹ and in 2010 O´Leary and Bots,² established B-mode imaging as a useful tool for detecting and monitoring changes in intimal plus medial thickness. This method allows for the evaluation of changes in the arterial wall in areas without localized plaques. Therefore, carotid intima-media thickness (CIMT) measurements have been assessed in several observational and interventional studies. The noninvasive nature of B-mode imaging has made it popular for use in the pre-clinical diagnosis and follow-up of patients with atherosclerosis.^3-5

The assessment of cardiovascular risk in pediatric patients is challenging. Cardiovascular events or death rarely occur in children, but changes in the cardiovascular system can be identified at an early age in pediatric populations.⁶ CIMT has been shown to be increased in children with traditional cardiovascular risk factors, such as obesity, hypertension, and chronic kidney disease, as compared to healthy children.^7,8 However, previous studies assessing sex differences in CIMT in healthy pediatric populations have generated conflicting results.^9-11 These conflicts are probably secondary to the methodologies applied and the fact that the studies included children older than 10 years and adults in the same analyses.¹⁰

Consequently, the aim of the present study was to evaluate the influence of sex, age, and BMI on CIMT, and to establish parameters for CIMT in healthy children and adolescents aged 1 to 15 years.

Methods

Subjects

We selected 280 consecutive healthy Caucasian children and adolescents (males, n=175; mean age, 7.49±3.57 years), who underwent echocardiography for assessment of an innocent cardiac murmur referred by a private pediatrician. The population in the present study was part of the private health care system.

Exclusion criteria were children diagnosed with diabetes, dyslipidemia, hypertension, any systemic disease, and those considered overweight or obese (≥ 85th percentile) for their age.^12,13

Children were not sedated before the exams. Children who refused to undergo the ultrasound examination and those who did not allow a proper or complete examination, such as very young children, were excluded from the study.

Before the exam, the ultrasonographist collected information on demographic characteristics and cardiovascular risk factors of each parent. Parents were asked about the presence of hypertension, diabetes mellitus, dyslipidemia, coronary artery disease (CAD), and current smoking habit.

Hypertension was defined as a history of treated hypertension. Smoking history was coded as never or current smoker. Subjects were classified as having diabetes when treated for insulin-dependent or non-insulin-dependent diabetes. The use of lipid-lowering drugs was assessed. A history of myocardial infarction, angioplasty or coronary artery bypass graft surgery was recorded, and a positive CAD history was defined as the presence of any of these diseases. Children from parents under treatment for any of these diseases aforementioned were excluded from the study.

The subjects were divided into 3 groups according to age: 1 to 5 years (GI), 6 to 10 years (GII), and 11 to 15 years (GIII). Institutional ethical committee approval was obtained for the study. The legal representative of each child provided written informed consent before examination. Children older than 10 years also signed a consent form.

Ultrasound measurements

All CIMT measurements were made using high-resolution B-mode ultrasonography (Philips Medical Systems' HD11 platform) with a broadband width linear array transducer L 3-12 MHz. Sonography and readings were conducted by a trained and certified sonographer. The subjects were examined in the supine position with the neck extended and the probe in the anterolateral position. On longitudinal 2D ultrasound images of the carotid artery, the near wall and the far wall are displayed as 2 echogenic lines (the adventitia and intima) that are separated by the hypoechoic media. The distance between the leading edge of the first bright line of the far wall (lumen-intima interface) and the leading edge of the second bright line (media-adventitia interface) is defined as the CIMT.

For this study, we measured the CIMT on the distal 10 mm of the far wall of both the right and left common carotid artery. After zooming and freezing the image, we manually measured the CIMT using electronic calipers. Five measurements were recorded on each side and the average of these measurements was used for the final CIMT analyses.

Statistical analysis

Quantitative variables are described by mean, median, minimum, and maximum values and standard deviation. Qualitative variables are described as frequencies and percentages. Kolmogorov-Smirnov test was used to test the normality of the distribution. CIMT measurements of both sexes were compared using Student t test for independent samples. The age groups were compared using the analysis of variance model with one parameter (ANOVA) and the least significance difference for multiple comparisons. Pearson correlation coefficient was used to evaluate the linear association between CIMT and BMI. Multivariate analysis was performed by adjusting a multiple linear regression model using CIMT as the dependent variable and sex, age, and BMI as independent variables. A p-value < 0.05 indicated statistical significance. The sample size was not calculated at the present study because there are no normative values for CIM in healthy children and adolescents. Data were analyzed with the SPSS v. 20.0 computer program.

Results

This study included 280 healthy children and adolescents (males, n=175; mean age, 7.49±3.57 years; mean BMI, 17.94±4.1 kg/m²; mean CIMT, 0.43±0.06 mm). Their characteristics are provided in Table 1. No significant differences in CIMT values were observed between male and female children and adolescents in the total population or among the age groups (Table 2). CIMT was not correlated to BMI in the total population or among the age groups (Table 2). Subjects older than 10 years had the highest CIMT values (Tables 1 and 2, Figure 1).

Table 1
General characteristics of the study population

Groups	N (%)	Male/Female (n)	BMI (kg/m2; mean±SD)	CIMT (mm; mean±SD)	*p
GI	93 (33.2%)	57/36	16±3	0.42±0.06
GII	127 (45.4%)	78/49	17.9±3.7	0.42±0.05
GIII	60 (21.4%)	40/20	20.9±4.5	0.45±0.05
Total	280	175/105	17.94±4.1	0.43±0.06	0.013
Groups					†P
GI vs GII					0.615
GI vs GIII					0.02
GII vs GIII					0.004

• BMI: body mass index; CIMT: carotid intima-media thickness; SD: standard deviation. GI = 1 to 5 years; GII = 6 to 10 years; GIII = 11 to 15 years.
• ^*
  Analysis of variance with one parameter, p < 0.05.
• ^†
  Least significant diference test, p < 0.05.

Table 2
Correlations between carotid intima-media thickness (CIMT), sex and body mass index (BMI) among age groups and in the entire study population

Age (years)	Sex	N	CIMT (mm; mean±SD)	*P	†BMI	p
1 a 5	Male	57	0.43±0.06
	Female	36	0.42±0.05	0.62	0.17	0.11
6 a 10	Male	78	0.42±0.05
	Female	49	0.41±0.05	0.23	0.01	0.91
11 a 15	Male	40	0.45±0.05
	Female	20	0.45±0.05	0.98	-0.01	0.92
Total	Male+Female	280			0.11	0.056
	Male	175	0.43±0.06		0.12	0.127
	Female	105	0.42±0.05	0.243	0.10	0.32

• SD: standard deviation.
• ^*
  Student t test for independent samples.
• ^†
  Pearson correlation coefficient.

Figure 1
Carotid intima-media thickness (CIMT) among age groups.

Discussion

Much information is available concerning CIMT in adults, but little information exists regarding CIMT in healthy pediatric populations, despite the need for early detection and prevention of cardiovascular disease.⁹ Most studies of CIMT in pediatric patients have compared healthy children with children who have cardiovascular risk factors, such as hypertension, diabetes, dyslipidemia, obesity, and metabolic syndrome. Additionally, most studies have included subjects aged 10 years or older.^14-16

In the present study we only included subjects younger than 15 years, and we found that in very young (<10 years old) healthy children, we were unable to detect any significant difference in CIMT when we considered sex and BMI as independent variables. These findings agree with previous studies^2,6-16 that concluded that the normal carotid arterial wall is unaffected by age or sex until approximately 18 years of age, after which time, there is diffuse progressive intimal thickening. However, we cannot exclude the possibility that our results could be due to the fact that the imaging method used here (high-resolution B mode ultrasonography) is not able to detect such small differences in CIMT due to its low sensitivity. In our study, we confirmed that, as in adults,¹⁷ CIMT increases with age. These findings could be related to the fact that, by the age of 10, most boys and girls are beginning puberty and undergoing hormonal changes that induce a significant increase in total body fat percentage.^9,18

Other possible explanation is that CIMT increases as a physiological reaction of the vessel to adapt the age-dependent rise in blood pressure.⁶ In fact, CIMT changes could reflect non-atherosclerotic and adaptive responses to aging and mechanical stress.^6,19 In the present study, we only included healthy children with normal BMI. CIMT appears to coincide with the normal development of children and increases with age, as it does in adults. Koçyiğit et al.²⁰ have studied 91 healthy children aged 7 to 15 years and observed an age-related physiologic thickening of the carotid intima-media that was not related to sex. CIMT is considered a reflection of multiple risk factors, but primary contributors to intima-media thickening are age and hypertension, which do not necessarily reflect the atherosclerotic process.^21-23 Some studies have corroborated these findings. Lande et al.¹⁴ have concluded that CIMT is increased in childhood primary hypertension and is independent of the effects of obesity.

Di Pino et al.²⁴ have reported that subjects with altered glucose tolerance had associated morphological and functional alterations of the arterial wall; however, these alterations are not likely to be related to hyperglycemia, but, instead, related primarily to aging. Opposing results have also been reported. For example, Stabouli et al.²⁵ have studied a similarly aged population and observed that obese children and adolescents have greater CIMT than non-obese subjects, independent of blood pressure. Giannini et al.²⁶ have concluded that both obese and thin children present early signs of atherosclerosis, including increased oxidative stress, impaired inflammation, and insulin sensitivity, as well as increased CIMT values.

Pediatric epidemiological studies, as well as case-control and observational studies in children, have confirmed that CIMT is increased in the presence of risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity.^15-16,27-29 Further, traditional cardiovascular risk factors already present in childhood predict the occurrence of preclinical carotid atherosclerosis in adulthood.^30,31 However, the availability of normative CIMT data for children is limited and most studies have compared CIMT values from children with those from adult populations. Therefore, in the present study, we attempted to assess CIMT in healthy children and adolescents between 1 and 15 years, and to fill a major gap in medical pediatric literature. Our findings could be used to evaluate other children of the same age with comorbidities, such as obesity, hypertension, diabetes mellitus, and dyslipidemia, and children whose parents have cardiovascular risk factors.

Conclusion

Among healthy children younger than 15 years, there is no significant difference in CIMT between males and females. BMI was not correlated to CIMT in healthy children under the age of 15 years. CIMT is constant in children younger than 10 years, regardless of sex and BMI. CIMT increases after the age of 10 years.

• Sources of Funding
  There were no external funding sources for this study.
• Study Association
  This article is part of the thesis of Post Doctoral submitted by Liz Andréa Villela Baroncini, from Pontifícia Universidade Católica do Paraná.

References

• ¹
  Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986;74(6):1399-406.
• ²
  O'Leary DH, Bots ML. Imaging of atherosclerosis: carotid intima-media thickness. Eur Heart J. 2010;31(14):1682-9.
• ³
  Simon A, Gariepy J, Chironi G, Megnien JL, Levenson G. Intima-media thickness, a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens. 2002;20(2):159-69.
• ⁴
  Hurst RT, Ng DW, Kendall C, Khandheria B. Clinical use of carotid intima-media thickness: review of the literature. J Am Soc Echocardiogr. 2007;20(7):907-14.
• ⁵
  Gepner AD, Keevil JG, Wyman RA, Korcarz CE, Aeschlimann SE, Busse KL, et al. Use of carotid intima-media thickness and vascular age to modify cardiovascular risk prediction. J Am Soc Echocardiogr. 2006;19(9):1170-4.
• ⁶
  Doyon A, Kracht D, Bayazit AK, Deveci M, Duzova A, Krmar RT, et al; 4C Reference Study Consortium. Carotid artery intima-media thickness and distensibility in children and adolescents: reference values and role of body dimensions. Hypertension. 2014;63(5):e121-2.
• ⁷
  Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, et al; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment of clinical research: a scientific statement from the American Heart Association. Hypertension. 2009;54(5):919-50. Erratum in: Hypertension. 2010;56(3):e36.
• ⁸
  Brady TM, Schneider MF, Flynn JT, Cox C, Samuels J, Saland J, et al. Carotid intima-media thickness in children with CKD: results from the CKiD study. Clin J Am Soc Nephrol. 2012;7(12):1930-7.
• ⁹
  Böhm B, Hartmann K, Buck M, Oberhoffer R. Sex differences of carotid intima-media thickness in healthy children and adolescents. Atherosclerosis. 2009;206(2):458-63.
• ¹⁰
  Sass C, Herbeth B, Chapet O, Siest G, Visviks S, Zannad F. Intima-media thickness and diameter of carotid and femoral arteries in children, adolescents and adults from the Stanislas cohort: effect of age, sex, anthropometry and blood pressure. J Hypertens. 1998;16(11):1593-602.
• ¹¹
  Jourdan C, Wuhl E, Litwin M, Fahr K, Trelewicz J, Jobs K, et al. Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents. J Hypertens 2005;23(9):1707-15.
• ¹²
  Conde WL, Monteiro CA. Body mass index cutoff points for evaluation of nutritional status in Brazilian children and adolescents. J Pediatr (Rio J). 2006;82(4):266-72.
• ¹³
  Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320(7244):1240-3.
• ¹⁴
  Lande MB, Carson NL, Roy J, Meagher CC. Effects of childhood primary hypertension on carotid intima media thickness: a matched controlled study. Hypertension. 2006;48(1):40-4.
• ¹⁵
  Schiel R, Beltschikow W, Radón S, Kramer G, Perenthaler T, Stein G. Increased carotid intima-media thickness and associations with cardiovascular risk factors in obese and overweight children and adolescents. Eur J Med Res. 2007;12(10):503-8.
• ¹⁶
  Järvisalo MJ, Putto-Laurila A, Jartti L, Lehtimäki T, Solakivi T, Rönnemaa T, et al. Carotid artery intima-media thickness in children with type 1 diabetes. Diabetes. 2002;51(2):493-8.
• ¹⁷
  Juonala M, Kähönen M, Laitinen T, Hutri-Kähönen N, Jokinen E, Taittonen L, et al. Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: the cardiovascular risk in Young Finns study. Eur Heart J. 2008;29(9):1198-206.
• ¹⁸
  Vizmanos B, Martí-Henneberg C. Puberty begins with a characteristic subcutaneous body fat mass in each sex. Eur J Clin Nutr. 2000;54(3):203-8.
• ¹⁹
  Iwakiri T, Yano Y, Sato Y, Hatakeyama K, Marutsuka K, Fujimoto S, et al. Usefulness of carotid intima-media thickness measurement as an indicator of generalized atherosclerosis: findings from autopsy analysis. Atherosclerosis 2012;225(2):359-62.
• ²⁰
  Koçyigit A, Dogan M, Yilmaz I, Çaglar M, Hatipoglu C, Koçyigt F, et al. Relation of age and sex with carotid intima media thickness in healthy children. Turk J Med Sci 2014;44(3):422-6.
• ²¹
  Finn AV, Kolodgie FD, Virmani R. Correlation between carotid intimal/medial thickness and atherosclerosis: a point of view from pathology. Arterioscler Thromb Vasc Biol. 2010;30(2):177-81.
• ²²
  Chironi J, Gariepy J, Denarie N, Balice M, Megnien JL, Levenson J, et al. Influence of hypertension on early carotid artery remodeling. Arterioscler Thromb Vasc Biol. 2003;23(8):1460-4.
• ²³
  Grau M, Subirana I, Agis A, Ramos R, Basagaña X, Martí R, et al. Carotid intima-media thickness in the spanish population: reference ranges and association with cardiovascular risk factors. Rev Esp Cardiol (Engl Cardiol). 2012;65(12):1086-93.
• ²⁴
  Di Pino A, Alagona C, Piro S, Calanna S, Spadaro L, Palermo F, et al. Separate impact of metabolic syndrome and altered glucose tolerance on early markers of vascular injury. Atherosclerosis. 2012; 223(2):458-62.
• ²⁵
  Stabouli S, Kotsis V, Karagianni C, Zakopoulos N, Konstantopoulos A. Blood pressure and carotid intima-media thickness in children and adolescents: the role of obesity. Hellenic J Cardiol. 2012;53(1):41-7.
• ²⁶
  Giannini C, de Giorgis T, Scarinci A, Cataldo I, Marcovecchio ML, Chiarelli F, et al. Increased carotid intima-media thickness in pre-pubertal children with constitutional leanness and severe obesity: the speculative role of insulin sensitivity, oxidant status, and chronic inflammation. Eur J Endocrinol. 2009;161(1):73-80.
• ²⁷
  Fang J, Zhang JP, Luo CX, Yu XM, Lv LQ. Carotid intima-media thickness in childhood and adolescent obesity relations to abdominal obesity, high triglyceride level and insulin resistance. Int J Med. 2010;7(5):278-83.
• ²⁸
  Reinehr T, Kiess W, de Sousa G, Stoffel-Wagner B, Wunsch R. Intima media thickness in childhood obesity: relations to inflammatory marker, glucose metabolism, and blood pressure. Metabolism 2006;55(1):113-8.
• ²⁹
  Le J, Zhang D, Menees S, Chen J, Raghuveer G. "Vascular age" is advanced in children with atherosclerosis-promoting risk factors. Circ Cardiovasc Imaging. 2010;3(1):8-14.
• ³⁰
  Laitinen TT, Pahkala K, Magnussen CG, Viikari JS, Oikonen M, Taittonen L, et al. Ideal cardiovascular health in childhood and cardiometabolic outcomes in adulthood: the cardiovascular risk in Young Finns Study. Circulation. 2012;125(16):1971-8.
• ³¹
  Wilson AC, Mitsnefes MM. Cardiovascular disease in CKD in children: update on risk factors, risk assessment, and management. Am J Kidney Dis. 2009;54(2):345-60.

Publication Dates

• Publication in this collection
  08 Mar 2016
• Date of issue
  Apr 2016

History

• Received
  13 June 2015
• Reviewed
  29 Nov 2015
• Accepted
  30 Nov 2015