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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:984-991

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:984.)
© 1996 American Heart Association, Inc.

Articles

Risk Factors Related to Carotid Intima-Media Thickness and Plaque in Children With Familial Hypercholesterolemia and Control Subjects

Serena Tonstad; Oddmund Joakimsen; Eva Stensland-Bugge; Trond P. Leren; Leiv Ose; David Russell; Kaare H. Bønaa

the Lipid Clinic, Medical Department A (S.T., L.O.) and the Department of Neurology (D.R.), National Hospital, Oslo; the Institute of Community Medicine, University of Tromsø (O.J., E.S-B., K.H.B.); and the Department of Medical Genetics, Ulleva°l University Hospital, Oslo (T.P.L), Norway.

Correspondence to S. Tonstad, MD, MPH, Lipid Clinic, Rikshospitalet, N-0027 Oslo, Norway. E-mail serena.tonstad@rh.uio.no.

Abstract

To assess the relationship between risk factors for cardiovascular disease and early atherosclerotic changes in the carotid artery, we measured carotid intima-media thickness by B-mode ultrasonography in 61 boys and 29 girls 10 to 19 years old with familial hypercholesterolemia (FH) and 30 control subjects matched for age and sex. All were nonsmokers, and all the FH adolescents had a known mutation in the LDL receptor gene. Mean intima-media thickness in the far wall of the carotid bulb was greater (P=.03) in the FH group than in the control subjects: 0.54 mm (95% confidence interval [CI], 0.52 to 0.56) versus 0.50 mm (95% CI, 0.47 to 0.52). In the entire group, mean and maximum intima-media thicknesses in the carotid bulb were positively associated with levels of apolipoprotein B and fibrinogen after control for pubertal stage (r=.19 to .24; P<.05), as was male sex. Plasma total homocysteine was similar in the FH and control groups and was associated with mean and maximum intima-media thicknesses in the far wall of the common carotid artery and carotid bulb after control for pubertal stage (r=.22 to .28; P<.05). With the exception of the relation between plasma fibrinogen level and mean carotid bulb intima-media thickness, these associations were essentially unchanged in stepwise multiple linear regression analyses, allowing for the entry of BMI and level of HDL cholesterol into the analysis. Carotid artery plaque was present in 10% of the children with FH versus none of the control subjects. Children with plaque had a higher mean cholesterol-years score than children without plaque. These findings suggest that the classic lipid and hemostatic risk factors as well as plasma total homocysteine are associated with markers of early carotid atherosclerosis from the second decade of life. B-mode ultrasonography may prove to be a useful tool in risk stratification of children with FH.


Key Words: familial hypercholesterolemia • homocys-teine • carotid arteries • children • ultrasonography

Guidelines agree that children with FH should receive dietary treatment and, in some cases, cholesterol-lowering drugs for elevated levels of LDL cholesterol.1 2 Although lowering LDL cholesterol levels is expected to reduce the child's future risk of cardiovascular disease, therapy with a low-fat diet and bile acid sequestrants requires careful follow-up,3 succeeds in only a minority,4 and may not be needed for all children with FH. Potent cholesterol-lowering drugs reverse the risk of cardiovascular disease due to hypercholesterolemia relatively rapidly in adults.5 Drug therapy may therefore be limited to children at exceptional risk.6 Both the family history and level of LDL cholesterol are important determinants of risk7 8 ; however, these factors cannot completely predict its extent.8 9

In adults, noninvasive methods for evaluating carotid arterial wall thickness may identify subjects with more generalized atherosclerosis, who are at risk for coronary heart disease.10 11 The intima-media thickness of the carotid arteries, assessed by B-mode ultrasonography, has been shown to be prospectively associated with the risk of myocardial infarction.12 Intima-media thickening and carotid plaque are associated with levels of atherogenic lipids and lipoproteins, plasma total homocysteine, and hemostatic factors, in addition to the established factors of age, male sex, smoking, diabetes mellitus, and hypertension.13 14 15 16 17 18 These relations have not been widely studied in children, although the childhood years may provide data that are relatively unobscured by disease or lifestyle habits. To date, one study reported that young children with hypercholesterolemia had a thicker carotid intima-media complex compared with control subjects, but arterial thickness was not associated with serum cholesterol levels.19

In the present study, we used B-mode ultrasonography to examine nonsmoking, normotensive children with FH to see which clinical and laboratory variables were associated with carotid intima-media thickening and the presence of plaque. The diagnosis of FH was based on the presence of a specific LDL receptor mutation. Because autopsy studies indicate that atherosclerotic changes in arteries begin around the age of 10 years,20 we chose the age group of 10 to 19 years. The results were compared with findings in a group of healthy control subjects.

Methods

Subjects
Ninety-one children 10 to 19 years old with FH, nonusers of tobacco according to the clinic chart, were asked to take part. One boy smoked cigarettes daily and was excluded, leaving 29 girls and 61 boys, of whom 76 were not known to be related to the second degree. The diagnosis of FH had been made a mean of 6 years previously (range, 1 to 11 years). Two had tendon xanthoma. None had arcus corneae or xanthelasma. Dietary recommendations to limit total fat to <=30% of total calories and saturated fat to <10% of total calories were given at the time of the initial diagnosis and reinforced at all subsequent clinic visits. Twenty-four (27%) of the subjects took a bile acid sequestrant in doses of 4 to 8 g (cholestyramine) or 5 to 10 g (colestipol). The bile acid sequestrant had been taken for 1 to 7 years (median, 2 years). None used oral contraceptives or other drugs that affect lipid metabolism.

In all subjects, FH was caused by a specific mutation in the LDL receptor gene. Forty-nine (54%) had FHElverum, a point mutation in the first nucleotide of intron 3 of the LDL receptor gene21 ; 17 (19%) had FHC210G, a point mutation in exon 4 replacing a cysteine residue with glycine22 ; 15 (17%) had FHSvartor, a point mutation creating a stop codon at codon 78 in exon 321 ; and in 9, the mutation was one of several other mutations, including FHGujerat (2 subjects),23 FHCincinnati-5 (3 subjects),23 FHPadova (1 subject),23 FHSkjetten (1 subject),24 and two novel mutations in the EGF precursor homology domain of the LDL receptor gene (FH{Delta}N466 and FHintron 11+1,G-->T, 1 subject each).25 The distribution of mutations was similar to that of the general Norwegian FH population.21 22 24

Children who did not require >1 hour of travel to the clinic were asked to invite a friend of the same sex and about the same age, not known to have hypercholesterolemia or chronic disease, to take part in the study. Of 33 friends, 2 were daily smokers and 1 refused the blood test, leaving 20 boys and 10 girls who made up the control group. Informed consent was obtained from all participants. The study was approved by the regional medical board for medical ethics.

Height and weight were measured in all subjects by the same observer with a wall-mounted stadiometer and an electronic scale. BMI was calculated, and Tanner's pubertal stage was noted.26 Of the entire group, 28.3% were prepubertal (Tanner's stage 1), 30.8% were in stage 2, and 40.9% were in stages 3 through 5. Blood pressure was measured in the right arm with a mercury sphygmomanometer. The medical chart was reviewed to obtain all previous lipid and lipoprotein measurements. Subjects with FH had a mean of 10 (range, 1 to 20) previous serum lipid profiles (cholesterol, HDL cholesterol, triglyceride, and LDL cholesterol [calculated by the Friedewald formula]) that had been performed at intervals of >=2 months at one of two laboratories that used similar methodology, including the laboratory used in the present study. Apolipoprotein measurements done at the laboratory used in the present study were available for about one half of those measurements. The mean of these lipid and apolipoprotein values was calculated and is referred to as the lifetime value. In addition, we calculated a cholesterol-years score for each subject. As described previously,27 the total cholesterol level (in millimoles per liter) of each patient at the time of original diagnosis was multiplied by the age of the patient at diagnosis. The mean level during treatment with diet and/or bile acid sequestrants was multiplied by the number of years of treatment. The pretreatment and posttreatment cholesterol-years (millimole-years per liter) were then added together for the total cholesterol-years score. For control subjects, the first component was calculated.

Family history data were obtained from the chart of the parent with FH. The presence of premature cardiovascular disease was based on hospital or physician reports of one or more of the following events before the age of 50 years: sudden cardiac death, typical exercise-induced angina pectoris, myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, cardiac transplant, or cerebral infarction.

Laboratory Analyses
After an overnight fast, blood samples were obtained by venipuncture from all subjects. Serum total cholesterol and triglyceride levels were determined by enzymatic methods. HDL cholesterol was determined after precipitation by heparin and MnCl2. LDL cholesterol was calculated by the Friedewald formula. Apo B and apo A-I were measured by rate nephelometry. Lp(a) was measured by the Behring nephelometric analyzer. The limit of detection was 100 mg/L. Plasma fibrinogen was measured by an automated clotting assay. Apo E genotyping was performed only on children with FH, by the method described by Eiklid and Leren.28

For analysis of plasma total homocysteine, EDTA samples were immediately placed on ice. The plasma was separated within 30 minutes and stored at -20°C until analysis. Total homocysteine, referring to the sum of protein-bound, free oxidized, and reduced species of homocysteine, was measured by a modification of a fully automated assay based on precolumn derivatization followed by reverse-phase high-performance liquid chromatography.29 30 Total homocysteine levels were missing for five control subjects because of insufficient amounts of plasma.

Carotid Ultrasonography
All examinations were done by the same sonographer (O.J.), who was blinded to the participants' case status and risk factor levels. High-resolution B-mode ultrasonography of the right carotid artery was performed with an Acuson Xp12 ultrasound scanner equipped with a linear 5- to 7-MHz transducer. The subjects were examined in the supine position with the head turned slightly to the left. The common, internal, and external carotid arteries were identified by combined B-mode and color Doppler ultrasound examinations.

A careful search was performed to obtain an optimal visualization of the vessel wall demonstrating the typical double lines representing the intima-media layer. Intima-media thickness was defined as the distance between the leading edge of the lumen-intima interface of the far wall and the leading edge of the media-adventitia interface of the far wall. Three separate images of longitudinal transaxial views obtained from both the proximal 10 mm of the carotid bulb and the distal 10 mm of the common carotid artery were frozen on the R wave of the electrocardiogram (end diastole) and stored on videotape.

The frozen images were then digitized off-line and displayed on a screen by use of commercially available software.31 The intima-media thickness was measured on each of the three frozen images in a standardized manner as described by Wendelhag et al.31 The measurements were performed by a trained vascular technician who was blinded to the participants' case status and risk factor levels.

Mean and maximum intima-media thicknesses of the common carotid artery far wall and mean and maximum intima-media thicknesses of the carotid bulb far wall were the variables of primary interest in the present study. Interobserver and intraobserver variability (including the sum of variation in data collection and measurements) studied in our laboratory with repeated recordings has shown coefficients of variation for mean intima-media thickness of 6.5% and 5.3%, respectively.

The near and far walls of the common carotid artery, the carotid bulb, and the internal carotid artery were scanned for the presence of atherosclerotic plaques, defined as a distinct area of the vessel wall protruding into the lumen >50% of the adjacent parts of the intima-media layer. Plaques of the near and far walls of the three segments of the carotid artery were identified and recorded.

Statistical Analyses
Variables that were not normally distributed, including triglycerides, total homocysteine, fibrinogen, and mean and maximum intima-media thicknesses in the carotid bulb were logarithmically transformed before analysis. Subjects were classified into two groups according to level of Lp(a): high levels were >=300 mg/L, and low levels were <300 mg/L. This cutoff level was based on previously published evidence32 and was equivalent to the 75th percentile in a population-based sample of 8- to 12-year-old children in Oslo.33

Continuous variables were compared by t tests for paired or unpaired samples, as appropriate. Categorical variables were compared with the {chi}2 test. Partial correlation coefficients between carotid measurements and cardiovascular risk factors were controlled for pubertal stage, because several risk factor levels, including lipid, lipoprotein, and homocysteine levels, are influenced by pubertal onset. Variables showing a significant or near-significant relation (P<=.05) to one or more carotid measurements after pubertal stage was controlled for were included in multivariate analyses to assess independent associations. Because of the correlation between LDL cholesterol and apo B levels (r=.97; P=.0001) and between HDL cholesterol and apo A-I (r=.88; P=.0001), only one from each set of variables was chosen. In stepwise multiple regression analyses with intima-media thickness as the dependent variable, pubertal stage was forced into the equation before the rest of the variables (total homocysteine, fibrinogen, apo B, HDL cholesterol, BMI, and sex).

To compare intima-media thicknesses according to the specific LDL receptor mutations, one subject was chosen at random from each group of children known to be related to avoid confounding by other genetic factors. Thus, 42 subjects were chosen from FHElverum, 14 from FHC210G, and 11 from FHSvartor. These groups were compared by one-way ANOVA.

All analyses were performed on a desktop computer using Statview II programs. Two-sided values of P<.05 were considered statistically significant.

Results

The distributions of age and anthropometric measures were similar in children with FH and control subjects (Table 1Down). No subject had blood pressure levels >=140/90 mm Hg. Levels of atherogenic lipids and lipoproteins were higher in boys and girls with FH, triglyceride levels were higher in boys with FH, and levels of HDL cholesterol were lower in boys and girls with FH than in control subjects (Table 2Down). Levels of total homocysteine and fibrinogen were similar in both groups. In the entire group, fibrinogen was related to BMI and levels of HDL cholesterol and triglycerides (r=.29, -.29, and .27, respectively; P<=.004). Plasma total homocysteine was related to pubertal stage (r=.28; P=.003) but not to other variables.


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  		Table 1. Characteristics of Children With FH and Control Subjects


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  		Table 2. Levels of Lipids, Apolipoproteins, Plasma Total Homocysteine, and Fibrinogen in FH and Control Subjects

Mean and maximum intima-media thicknesses in the far wall of the common carotid artery and the carotid bulb were slightly greater in boys than girls with FH, although not significantly so (Table 3Down). Intima-media thicknesses from two of the four carotid sites were greater in boys than in girls in the control group. Mean common carotid bulb intima-media thickness was significantly greater in children with FH than in control subjects (0.54 mm; 95% CI, 0.52 to 0.56 versus 0.50 mm; 95% CI, 0.47 to 0.52). Carotid intima-media thicknesses did not differ between FH subjects who had a parent with premature cardiovascular disease and the rest of the FH subjects (data not shown).


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  		Table 3. Carotid Intima-Media Thickness in Children With FH and Control Subjects

Of subjects with FH, 42% had high levels of Lp(a), but only 20% of control subjects had high levels (P=.049). Mean intima-media thicknesses were not significantly associated with Lp(a) level after control for FH or control status (data not shown; P>=.08).

In subjects with FH, total homocysteine was related to all four carotid intima-media thickness measurements (r=.20 to .28; P<=.05). In control subjects, total homocysteine was significantly related to mean and maximum intima-media thicknesses in the common carotid only (r=.41 and .48, respectively; P<.05). In the entire group, total homocysteine was related to intima-media thicknesses at all four carotid sites before and after adjustment for pubertal stage (Table 4Down). Fibrinogen was related to intima-media thickness at three of the four carotid sites. Levels of LDL cholesterol and apo B but not levels of HDL cholesterol or apo A-I were related to mean intima-media thickness in the carotid bulb, and apo B was also related to the maximum intima-media thickness in the carotid bulb. Triglyceride level was not related to intima-media thicknesses (r<=.14; P>.10). Male sex was associated with greater intima-media thickness in the carotid bulb (Table 4Down), although the relationship was somewhat weakened when adjusted for BMI (mean thickness: r=.20, P=.06; maximum thickness: r=.21, P=.045). These relationships were essentially unchanged in the stepwise multiple regression analyses, in which male sex and higher levels of total homocysteine, apo B, and fibrinogen were associated with one or more carotid measurements (Table 5Down). Lifetime levels of LDL cholesterol and apo B were related to the levels obtained in the present study (r=.67 to .77; P=.0001) and showed correlations with carotid measurements similar to those with the study values (data not shown).


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  		Table 4. Correlation Coefficients Between Carotid Intima-Media Thickness and Cardiovascular Risk Factors, Unadjusted and Adjusted for Pubertal Stage (All Children; n=115 to 120)


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  		Table 5. Variables Associated With Four Measurements of Carotid Intima-Media Thickness in All Subjects in Stepwise Multiple Regression Analyses (After Control for Pubertal Stage)

Of the FH subjects, 61% had the apo E 3/3 genotype, 23% had E 3/4, 9% had E 3/2, and the rest had E 4/4 or 4/2. Serum triglyceride level was higher in the apo E 3/2 group than in the E 3/3 group (1.8±1.0 versus 1.0±0.5 mmol/L; P<.05). Other lipid levels and carotid intima-media thicknesses did not differ between the apo E groups (data not shown).

LDL cholesterol levels did not differ according to the LDL receptor mutation (6.7±1.6, 6.5±1.3, 6.8±1.3, and 5.6±1.2 mmol/L in the FHElverum, FHC210G, FHSvartor, and other groups, respectively; P>.10). Carotid bulb mean and maximum intima-media thicknesses were 0.56±0.11 and 0.71±0.18, 0.54±0.09 and 0.71±0.20, and 0.51±0.07 and 0.63±0.12 mm in the FHElverum, FHC210G, and FHSvartor groups, respectively (not significant). Common carotid mean and maximum intima-media thicknesses were 0.48±0.07 and 0.58±0.09, 0.49±0.06 and 0.59±0.08, and 0.47±0.08 and 0.58±0.12 mm in the FHElverum, FHC210G, and FHSvartor groups, respectively (not significant).

Subjects who took bile acid sequestrants did not differ in mean age, height, weight, or distribution of sex from the rest of the group with FH (Table 6Down). They had lower LDL cholesterol, apo B, and lifetime LDL cholesterol levels but carotid intima-media thicknesses similar to those of subjects not taking bile acid sequestrants. There was a trend toward higher total homocysteine levels in the group taking sequestrants.


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  		Table 6. Characteristics of FH Children Taking or Not Taking Bile Acid Binding Resins

Carotid plaque was found in four girls and five boys with FH but in no control subjects. Plaque was located in the carotid bulb in all but one girl, in whom it was located in the internal carotid artery. Only one FH subject with plaque had a parent with premature cardiovascular disease. One boy had plaque in both the carotid bulb and the common carotid artery. Plaque thickness ranged from 0.8 to 1.3 mm. Children with plaque had higher lifetime total and LDL cholesterol and apo B levels and cholesterol-years score than the rest of the children with FH (Table 7Down).


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  		Table 7. Characteristics of FH Children With and Without Carotid Plaque

Discussion

This study establishes a modest but significant independent association between carotid artery intima-media thickness in the second decade of life and certain atherogenic risk factors, including male sex and levels of apo B and fibrinogen. Plasma total homocysteine was also independently correlated with carotid thickness measurements. Moreover, the presence of plaque, found in 10% of subjects with FH, was associated with higher lifetime levels of total and LDL cholesterol and apo B and cholesterol-years score.

Autopsy studies show that lipid deposition in the intima of the coronary arteries and aorta occurs from the first years of life onward. By puberty, fatty streaks appear to be gradually transformed into more advanced atherosclerotic lesions.20 A significant relationship between premortem or postmortem total and LDL cholesterol and the extent of intimal involvement has been shown in the Bogalusa Heart Study and the Pathobiological Determinants of Atherosclerosis in Youth program.34 35 The availability of noninvasive ultrasonographic assessment of arteries used in the present study extends autopsy data and demonstrates that carotid intima-media thickening and plaque may start in childhood, depending on the presence of classic and new cardiovascular risk factors.

LDL cholesterol and/or apo B levels have been associated with early atherosclerotic changes in the carotid arteries in virtually every study that has looked at the relationship,12 13 14 18 19 36 37 38 39 40 41 although the association may be weak in the elderly.42 These levels predict progression of atherosclerosis12 43 and, if lowered, cause regression or slower progression of intima-media thickening.44 45 46 Accordingly, the mean intima-media thickness of the common carotid artery was 0.13 mm greater in adults with FH than in matched control subjects with normal cholesterol levels.47 We found a difference of 0.04 mm in the mean intima-media thickness of the carotid bulb between children with DNA-confirmed FH and control subjects. The maximum intima-media thickness was also greater in the group with FH, but the difference did not reach statistical significance. In comparison, a difference of 0.03 mm in the maximum common carotid artery intima-media thickness was reported between hypercholesterolemic children in whom FH was not confirmed and control subjects in Italy.19 Although the difference between hypercholesterolemic and control subjects appears small, only the intima is involved in early atherosclerosis. Modest changes in its thickness may represent a substantial increase in atherosclerotic involvement.14 48

Our finding that plaque was present in 10% of children with FH may be compared with earlier observations in adult non-FH subjects. None of 257 men and women 18 to 29 years old participating in a population-based study were found to have carotid plaque.49 Among healthy female volunteers 45 to 54 years old, plaque was found in only 8.7%.37 Children with plaque had higher mean lifetime levels of LDL cholesterol and apo B and a higher cholesterol-years score but did not have a more severe family history. Current guidelines as to which children should receive drug treatment for hypercholesterolemia emphasize the importance of the family history but do not distinguish between children with high (>=4.1 mmol/L) or very high LDL cholesterol levels.1 6 None of the children with plaque had lifetime LDL cholesterol levels <=6.2 mmol/L or apo B levels <=1.6 g/L. Applying these cutoff points, we found plaque in 9 of 49 children (18%) in the first group and 9 of 62 children (15%) in the second group. On the basis of these findings, we suggest that the presence of lifetime LDL cholesterol levels >=6.3 mmol/L or apo B levels >=1.7 g/L in teenagers with FH may warrant screening for carotid plaque and intensified therapy to lower LDL cholesterol and apo B levels if plaque is found. Future studies involving repeated assessments of the arterial wall will be needed to test the usefulness of these cutoff points and the effect of treatment.

We have previously shown that lipid levels are similar in FH children carrying any of three Norwegian founder mutations, including those that cause putative null alleles (FHElverum and FHSvartor) or the production of a defective protein (FHC210G).50 This was confirmed in the present study. Thus, our finding that intima-media thicknesses were similar in the mutation groups suggests that the presence of a specific mutation affects early atherosclerosis through its effect on LDL, whereas the type of defect seems to occupy a lesser role.

HDL cholesterol and apo A-I levels were not related to intima-media thickness after control for pubertal stage or plaque. An inverse relationship between either or both levels and carotid atherosclerosis has been reported in some studies or subgroups of middle-aged or elderly subjects,37 39 40 although not in all.12 38 The severity of carotid stenosis assessed by duplex ultrasonography in subjects with FH was negatively associated with HDL cholesterol in one study.51 It has been suggested that the metabolism of triglyceride-rich lipoproteins and HDL affect later stenotic atherothrombotic processes, in contrast to LDL,14 which affects both early and late atherosclerosis.

Apo E genotype, which influences levels of triglycerides in our FH population (present study and Reference 47), was not associated with any carotid thickness measurement. The presence of an E4 allele, beyond its effect on increasing levels of LDL, predisposes to an increased number of atherosclerotic lesions in young men52 and is more frequent in youths with a paternal history of premature myocardial infarction.53 However, the effect of apo E polymorphism appears to be less pronounced in FH.54 The number of FH subjects carrying genotypes other than E3/3 was low and may limit the power of this study to detect differences.

Our data indicate that sex differences in atherosclerosis start early. When the prepubertal group (n=34) was examined separately, male sex remained associated with greater intima-media thickness (data not shown). However, the effect of sex appeared to be less prominent in the group with FH compared with control subjects, suggesting that the female advantage36 is attenuated in FH. Moreover, four of nine children with plaque were girls. Sex differences in rates of cardiovascular disease in FH are considerable,8 9 but sex differences in early atherosclerosis may be less prominent during adolescence than after sexual maturation is complete. The sex differences may be due in part to smaller carotid artery size in girls, because adjustment for BMI somewhat attenuated the association between sex and carotid measurements.

As expected, a greater proportion of children with FH than control subjects had elevated levels of Lp(a), but Lp(a) was not related to carotid intima-media thickness. This result is consistent with some earlier reports that found no relation between Lp(a) and early atherosclerosis49 and with the putative prothrombotic role of Lp(a) in cardiovascular disease. On the other hand, other evidence indicates that Lp(a) is related to the early stages of atherosclerosis,40 55 including patients with FH.56

A modest elevation of plasma total homocysteine has been shown to be a risk factor for carotid intima-media thickening and stenosis in addition to its association with myocardial infarction.15 57 58 We found that total homocysteine was related to all four carotid intima-media thickness measurements, and the association persisted in the multivariate analysis. No FH subjects or control subjects had levels >14.1 mmol/L, indicating that the increased risk was not related to the presence of a few subjects with extremely elevated levels. This finding is consistent with previous evidence that total homocysteine appears to be associated with increased cardiovascular risk within its normal range, with no apparent threshold effect.57 59

Total homocysteine tended to be higher in FH children taking bile acid-binding sequestrants. We did not measure vitamin levels in the present study, but we have previously shown that folate levels decrease during use of sequestrants.60 Sequestrants may elevate homocysteine levels by binding folate.61 Subjects taking sequestrants did not have lesser intima-media thicknesses, despite lower levels of LDL cholesterol and apo B; however, the duration of use was probably too short. In addition, the benefit of the lipid-lowering effect of sequestrants may be somewhat counteracted by their effect on homocysteine level. The subjects were not specifically advised to take folate. We suggest that folate supplementation during the use of sequestrants may be prudent, especially if levels of homocysteine increase. Cholesterol-lowering drugs other than sequestrants have not been used extensively in children. Although fibrates may present an advantage because of their fibrinogen-lowering property and reductase inhibitors lower LDL cholesterol levels more effectively than sequestrants, long-term safety has been documented only for sequestrants.62

Most lifestyle-dependent risk factors, particularly cigarette smoking, correlate with fibrinogen level and may confound the relationship between fibrinogen and atherosclerosis. In the present study, which excluded smokers, BMI, HDL cholesterol, and triglycerides showed the expected association with fibrinogen. However, fibrinogen was an independent determinant of intima-media thickness, in contrast to its correlates. This finding indicates that the measurement of fibrinogen in children may provide other risk information in addition to that obtained by measuring its correlates, as appears to be the case in adults.16 39 40 63

We found that the intima-media complex was thicker in the carotid bulb than in the common carotid artery and that plaque was located in the carotid bulb in eight of nine children. These findings are consistent with previous evidence showing that atherosclerotic lesions occur later in the common carotid artery than in the internal carotid artery or the carotid bulb.64 Carotid atherosclerotic lesions in younger subjects tend to occur in the same topographical locations as later, more advanced lesions.64 In adults with FH, an increase in the carotid intima-media thickness is at least a partial expression of more generalized atherosclerosis.65 Thus, the detection of early carotid artery changes may select children with FH who have a greater future risk of disease and greater benefit of early intervention.

Selected Abbreviations and Acronyms


apo = apolipoprotein
BMI = body mass index
CI = confidence interval
FH = familial hypercholesterolemia
Lp(a) = lipoprotein(a)

Acknowledgments

We thank Helga Refsum and Per M. Ueland for the analysis of plasma total homocysteine and Stein Evensen for suggesting the project and helpful comments.

Received November 9, 1995; revision received February 27, 1996; References

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