Iina Volanen

Endothelial Function in Healthy 11-Year-Old Children After Dietary Intervention With Onset in Infancy The Special Turku Coronary Risk Factor Intervention Project for Children (STRIP)

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.

Effect of 7-Year Infancy-Onset Dietary Intervention on Serum Lipoproteins and Lipoprotein Subclasses in Healthy Children in the Prospective, Randomized Special Turku Coronary Risk Factor Intervention Project for Children (STRIP) Study

Background—We previously showed that low-saturated-fat dietary intervention from infancy until 5 years of age safely and effectively reduced serum cholesterol concentration. We now report how such intervention influenced serum lipids, LDL particle size, and HDL subfractions in children when they reached the age of 7 years. Methods and Results—Healthy 7-month-old infants (n=1062) were randomized to the intervention (n=540) and control (n=522) groups. Each year, two individualized counseling sessions were organized to the intervention families. Serum lipid values were measured annually. The intervention boys had 0.20 to 0.39 mmol/L lower serum cholesterol values than the control boys throughout the follow-up (always P <0.05), but the values of the intervention and control girls did not differ. The LDL particle sizes and HDL subfractions were determined in a random subgroup of 96 intervention and 101 control children at the age of 7 years. The mean particle diameter of major LDL peak was 262.6 Å in the intervention boys and 258.5 Å in the control boys (P =0.05), and 259.2 Å in the intervention girls and 261.3 Å in the control girls (P =0.30). HDL2 and HDL3 cholesterol concentrations did not differ between the intervention and control children or between the two genders. Conclusions—The 7-year intervention favorably influenced not only the serum total and LDL cholesterol concentrations but also the LDL particle size in boys. LDL particle size remained unchanged in girls, as did HDL2 and HDL3 concentrations in both genders.

Arterial Intima-Media Thickness, Endothelial Function, and Apolipoproteins in Adolescents Frequently Exposed to Tobacco Smoke

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.

Development of antibodies against cytomegalovirus, varicella-zoster virus and herpes simplex virus in Finland during the first eight years of life: a prospective study.

To clarify when antibodies against cytomegalovirus (CMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV) develop among young children, 1206 serum samples collected prospectively from 199 children born in 1989 and 1990 were studied. The samples were drawn at the ages of 7 and 13 months, then yearly until the age of 5 y and then at 7 and 8 y. In each age group at least 106 samples were collected. Immunoglobulin G class antibodies to the 3 viruses were measured using an enzyme immunoassay. At the age of 7 months 27% of the children had CMVantibodies, whereas only 3% had antibodies against VZVand 2% against HSV. The prevalence of seropositivity for CMV increased slowly to 41% by the age of 8 y. Seroconversions to VZV antibody positivity occurred frequently after 2 y of age, so that by 8 y 83% of children had VZV antibodies. The proportion of children with HSV antibodies remained low throughout the study, as only 17% of children had HSV antibodies at the age of 8 y. The data show that HSV infection is becoming acquired later in life and the proportion of uninfected children is increasing. The proportion of CMV infections during the perinatal period and early infancy remains high, in one-third of the children, and most children also have VZV infection during the early years of life.

Decreased Aortic Elasticity in Healthy 11-Year-Old Children Exposed to Tobacco Smoke

OBJECTIVE. The goal was to assess the relationship between passive smoking and arterial elasticity in children. METHODS. Healthy 11-year-old children (N = 386) from an atherosclerosis prevention trial (Special Turku Coronary Risk Factor Intervention Project for Children) were studied. Aortic and carotid elasticities were determined by using M-mode ultrasound imaging based on measurements of blood pressure and arterial diameter changes during the cardiac cycle. The aortic stiffness index, Youngs elastic modulus, and distensibility and the respective indices for the carotid artery were calculated. Exposure to tobacco smoke was measured by using serum cotinine concentrations, and children were classified into 3 groups, that is, the noncotinine group (n = 220; undetectable cotinine levels), the low-cotinine group (n = 127; cotinine levels of 0.2–1.6 ng/mL), and the top-decile cotinine group (n = 39; cotinine levels of ≥1.7 ng/mL). RESULTS. Higher cotinine concentrations were associated with increased aortic stiffness index values. An increase in aortic Youngs elastic modulus and a decrease in aortic distensibility were observed across the cotinine groups. In multivariate regression models, the cotinine level remained a significant explanatory variable regarding all aortic elasticity indices. Carotid elasticity indices showed no differences across the cotinine groups. CONCLUSIONS. Childhood exposure to tobacco smoke (verified with serum cotinine levels) decreases aortic elastic properties in healthy children.

Increased Aortic Intima-Media Thickness in 11-Year-Old Healthy Children With Persistent Chlamydia pneumoniae Seropositivity

Objective—The relationship between Chlamydia pneumoniae (Cpn) infection and arterial measures of preclinical atherosclerosis has remained controversial. Because atherogenesis begins in early life, we examined whether carotid and aortic intima-media thickness (IMT) and brachial artery endothelial function are associated with Cpn seropositivity in children. Methods and Results—Cpn-specific IgG and IgA antibodies were assessed by enzyme immunoassay in 199 healthy children followed-up annually from 7 to 11 years of age. Carotid (cIMT) and aortic IMT (aIMT), and brachial artery flow-mediated dilatation (FMD) were measured in 137 of the 199 children at the age of 11 years using high-resolution ultrasound. Children with persistent IgG and/or IgA seropositivity to Cpn had significantly increased aIMT compared with seronegative children (IgG≤45 and IgA≤12 enzyme immunounits) or children with transient Cpn seropositivity (seronegative, 0.496 [0.054]; transient, 0.494 [0.061]; and persistent, 0.532 [0.086] mm; P<0.05 for trend). This trend was not explained by traditional atherosclerotic risk factors or pubertal stage. cIMT and FMD were not associated with Cpn seropositivity. Conclusions—Eleven-year-old children with persistent Cpn seropositivity show increased aIMT but not cIMT, suggesting that Cpn may affect the aortic wall, the site where the earliest atherosclerotic lesions are known to occur, in otherwise healthy children.

Arterial Intima-Media Thickness in 13-Year-Old Adolescents and Previous Antichlamydial Antimicrobial Use: A Retrospective Follow-up Study

BACKGROUND. Children with persistent Chlamydia pneumoniae infection may be at increased risk for atherosclerosis. The impact of antimicrobial therapy for primary prevention of atherosclerotic cardiovascular disease is unsolved. OBJECTIVE. The purpose of this study was to determine whether treatment with antimicrobial agents effective against C pneumoniae during childhood, regardless of indication, has a favorable influence on the arterial wall-thickness in children by the time they reach adolescence. SUBJECTS AND METHODS. The association of macrolide, tetracycline, quinolone, and rifamycin use (number of exposure events) between ages 5 and 13 years with carotid and aortic intima-media thickness at age 13 years was investigated among 508 healthy children. Information about the use of medications was obtained from the Finnish prescription register. Arterial intima-media thickness was measured with a high-resolution ultrasound. RESULTS. Mean aortic intima-media thickness showed a significant direct association with the number of antichlamydial antimicrobial exposure events also after controlling for established atherosclerotic risk factors. Elevated C-reactive protein level had an additional effect on aortic intima-media thickness in a multivariable model. Carotid intima-media thickness was not associated with the number of preceding antichlamydial treatments. CONCLUSIONS. Recurrent antichlamydial treatments in childhood have no favorable influence on early vascular changes but are associated with increased intima-media thickness in the abdominal aorta. These findings suggest that the use of antimicrobial agents does not offer protection against the potential atherogenicity of repeated infectious insults.

Serum Lipid Profiles Poorly Correlate With Chlamydia pneumoniae, Helicobacter pylori, and Cytomegalovirus Seropositivity in Prospectively Followed-Up Healthy Children

Objective—Chronic Chlamydia pneumoniae (Cpn), Helicobacter pylori (Hp), and herpes virus infections have been associated with atherogenic serum lipid profile and an excess of cardiovascular events in adults. Because mechanisms leading to atherosclerosis are active since early childhood, we examined whether Cpn, Hp, or cytomegalovirus (CMV) seropositivity relates to serum lipid, lipoprotein, or apolipoprotein concentrations in children. We also looked for factors increasing probability of Cpn seropositivity in children. Methods and Results—Cpn-specific IgG and IgA, as well as Hp-specific and CMV-specific IgG antibodies were assessed by enzyme immunoassay in 199 apparently healthy children, followed-up from 7 to 11 years of age. Serum lipid profiles were studied at the ages of 7, 9, and 11 years using standard methods. Neither seroconversion to Cpn IgG or IgA antibody positivity nor persistent seropositivity for Cpn, Hp, or CMV was associated with proatherogenic serum lipid values. Children with siblings were more likely to possess Cpn antibodies than children without siblings (IgG: OR, 5.24; 95% CI, 1.63 to 16.82; IgA: OR, 3.32; 95% CI, 1.15 to 9.57). Conclusions—These data suggest that contrary to the observations in adults, Cpn, Hp, and CMV seropositivity in otherwise healthy children is not associated with disturbances in serum lipid profile.

A Prospective Study of Chlamydia pneumoniae Antibodies in Children Between 7 months and 8 years of Age

To provide insight into the appearance and longitudinal course of Chlamydia pneumoniae antibodies in childhood, C. pneumoniae immunoglobulin G (IgG), IgA and, in selected children, IgM antibodies were measured annually in 199 healthy children, followed prospectively from age 7 months to age 8 y (number of samples 1225) using a commercial enzyme immunoassay kit. IgG antibodies to C. pneumoniae were common throughout the follow-up, and the values declined rapidly after apparent infections during early childhood. Of the 128 identified seroconversions, 94 were probably primary infections and 34 reinfections. IgM antibodies were detected in 28% of the samples that showed a clear increase in IgG. IgA antibodies were scarce before 2 y of age, but their proportion then increased gradually. At the ages of 7 and 8 y, 10% of the children had clearly positive IgG and IgA antibody values. Increases in IgG were not associated with clinical respiratory symptoms. This study shows that C. pneumoniae infections probably occur commonly already at an early age, and that the infections are often asymptomatic. Consecutive high IgG and IgA antibody concentrations at the ages of 7 and 8 y indicate that persistent seropositivity for both antibodies may already develop in young children.