Katariina Kallio

BACKGROUND: Passive smoking is associated with early arterial damage in adults, but its effect on endothelial function in children is unknown. METHODS AND RESULTS: Serum cotinine concentration was measured annually in children between 8 and 11 years of age who had participated since infancy in a randomized, prospective atherosclerosis prevention trial (Special Turku Coronary Risk Factor Intervention Project for children [STRIP]). At age 11, endothelium-dependent flow-mediated vasodilatory responses of the brachial artery were examined with high-resolution ultrasound in 402 children. These children were divided into 3 groups according to serum cotinine concentrations: the noncotinine group (nondetectable cotinine, n=229), the low cotinine group (cotinine between 0.2 and 1.6 ng/mL, n=134), and the top decile cotinine group (cotinine > or = 1.7 ng/mL, n=39). Longitudinal cotinine data in children aged 8 to 11 years and ultrasound studies were available in 327 children. At age 11, the increase in cotinine concentration was associated with attenuated peak flow-mediated dilation response (mean+/-SD: the noncotinine group 9.10+/-3.88%, the low-cotinine group 8.57+/-3.78%, and the top-decile cotinine group 7.73+/-3.85%; P=0.03 for trend). Similarly, total dilation response (the area under the dilation response versus time curve between 40 and 180 seconds after hyperemia) was affected by the cotinine level (P=0.02 for trend). These trends were not explained by traditional atherosclerosis risk factors. Arterial measures and passive smoking showed even stronger associations when longitudinal cotinine data were used (peak flow-mediated dilation, P=0.01 for trend; total dilation response, P=0.008 for trend). CONCLUSIONS: Exposure to environmental tobacco smoke confirmed by serum cotinine concentrations impairs endothelial function in a dose-dependent manner in 11-year-old children.

BACKGROUND: Exposure to tobacco smoke is associated with markers of preclinical atherosclerosis in adults, but its effect on arterial structure in adolescents is unknown. METHODS AND RESULTS: Healthy 13-year-old adolescents from the atherosclerosis prevention trial STRIP were studied. Maximum carotid and aortic intima-media thickness and brachial artery flow-mediated dilation were measured in 494 adolescents using high-resolution ultrasound. Serum lipid, lipoprotein, and apolipoprotein (Apo) A-I and B concentrations were determined using standard methods. Exposure to tobacco smoke was measured annually between ages 8 and 13 years using serum cotinine concentrations, analyzed with gas chromatography. To define longitudinal exposure, cotinine values of children having serum cotinine measured 2 to 6 times during follow-up were averaged and divided into tertiles (exposure groups): low (n=160), intermediate (n=171), and high (n=163). Adolescents with higher longitudinal exposure to tobacco smoke had increased carotid intima-media thickness (exposure groups [mean+/-SD]: low, 0.502+/-0.079 mm; intermediate, 0.525+/-0.070 mm; high, 0.535+/-0.066 mm; P<0.001) and increased aortic intima-media thickness (exposure groups: low, 0.527+/-0.113 mm; intermediate, 0.563+/-0.139 mm; high, 0.567+/-0.126 mm; P=0.008). The flow-mediated dilation decreased when cotinine level increased (exposure groups: low, 10.43+/-4.34%; intermediate, 9.78+/-4.38%; high, 8.82+/-4.14%; P=0.004). Moreover, ApoB (P=0.014) and ApoB/ApoA-I ratio (P=0.045) increased with increase in cotinine level. The associations between tobacco smoke exposure and ultrasound variables were unchanged after adjusting for traditional atherosclerosis risk factors and for ApoB. CONCLUSIONS: Frequent exposure to tobacco smoke is independently associated with arterial changes of preclinical atherosclerosis and increased ApoB levels among healthy adolescents. Clinical Trial Registration- clinicaltrials.gov. Identifier: NCT00223600.

To characterize brachial artery flow-mediated dilatation (FMD) in children, we monitored arterial diameter changes with ultrasound between 40 and 180 s after a 4.5-min forearm cuff occlusion-induced hyperemia in 105 healthy children (mean age, 11 yr; range, 9-16 yr). The peak FMD was 7.7 +/- 4.0% and occurred 79 +/- 33 s after cuff release. FMD at 60 s (5.3 +/- 4.0%) was significantly lower than the peak FMD (P < 0.0001). Twenty-three percent of the children (n = 24) reached peak FMD first after 110 s of postocclusion. Compared with others, these late responders weighed less, had smaller vessel size, and were more often girls, but had similar peak FMD. In multivariate analysis, FMD responses were inversely associated with brachial artery baseline diameter and serum cholesterol concentration. We conclude that the time to reach the peak FMD response in children varies considerably. When studying endothelial function in children with the use of the noninvasive ultrasound method, several brachial artery diameter measurements up to 120 s after cuff release are needed to determine the true FMD peak response.

BACKGROUND: Early childhood introduction of nutritional habits aimed at atherosclerosis prevention reduces children's serum total cholesterol concentration, but its effect on vascular endothelial function is unknown. METHODS AND RESULTS: Between 1990 and 1992, we randomized healthy 7-month-old infants (n=1062) to intervention (low-saturated-fat diet) and control (unrestricted diet) groups. At the age of 11 years, endothelium-dependent (flow-mediated) and endothelium-independent (nitrate-mediated) vasodilatory responses of the brachial artery were measured with high-resolution ultrasound in 179 intervention and 190 control children. The effect of intervention on endothelial function was significant in boys (P=0.0034) but not in girls (P=0.69). The maximum endothelium-dependent dilation response (mean+/-SD) was 9.62+/-3.53% and 8.36+/-3.85% in intervention boys and control boys and 8.84+/-4.00% and 8.44+/-3.60% in intervention girls and control girls, respectively. Intervention had no effect on nitrate-mediated dilation. The difference in endothelial function in boys remained significant after adjustment for current serum total or LDL cholesterol but became nonsignificant after adjustment for mean cholesterol measured under 3 years of age (adjusted means: 9.46% [CI 8.68% to 10.24%] versus 8.54% [CI 7.75% to 9.32%], P=0.11). CONCLUSIONS: A low-saturated-fat diet introduced in infancy and maintained during the first decade of life is associated with enhanced endothelial function in boys. The effect is explained in part by the diet-induced reduction in serum cholesterol concentration.