Published online before print February 28, 2008, doi: 10.1161/ATVBAHA.108.163329
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Associations of Dyslipidemias From Childhood to Adulthood With Carotid Intima-Media Thickness, Elasticity, and Brachial Flow-Mediated Dilatation in Adulthood
The Cardiovascular Risk in Young Finns Study
From the Centre of Applied and Preventive Cardiovascular Medicine (M.J., O.T.R.), and the Departments of Medicine (M.J., J.S.A.V., T.R.) and Clinical Physiology (O.T.R.), University of Turku; and the Department of Health and Functional Capacity (J.M., A.J., B.M.L.), National Public Health Institute, Turku, Finland.
Correspondence to Olli T. Raitakari, Department of Clinical Physiology, P.O. Box 52, 20521 Turku, Finland. E-mail olli.raitakari{at}utu.fi
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Dyslipidemias are the major cause for atherosclerosis. They may act synergistically with nonlipid risk factors to increase atherogenesis. In the present study, we examined the effects of dyslipidemias from childhood to adulthood and their interaction with nonlipid risk factors on markers of subclinical atherosclerosis.
Methods and Results— Study subjects were participants of the longitudinal Cardiovascular Risk in Young Finns Study started in 1980 (n=2265, age 3 to 18 years). To phenotype type IIa, IIb, and IV dyslipidemias and hypoHDL-cholesterolemia, we calculated age and sex-specific z scores for lipid values for each subject in 1980, 1983, 1986, and 2001. Subjects with mean z score over 90th percentile for LDL-cholesterol or triglycerides were considered having type IIa or IV dyslipidemia. Subjects with mean z score over 90th percentile for LDL-cholesterol and triglycerides had type IIb dyslipidemia, and those with mean z score below 10th percentile for HDL-cholesterol had hypoHDL-cholesterolemia. Compared to controls, subjects with type IIb dyslipidemia had increased carotid IMT (P<0.01). This difference remained significant when adjusted with other risk factors (P<0.05). Carotid IMT also increased significantly more with increasing number of nonlipid risk factors (P<0.001) or presence of the metabolic syndrome (P<0.05) in subjects with type IIb than in controls. Subjects with type IIb or type IV dyslipidemia had decreased carotid elasticity (P<0.05), but these differences became nonsignificant (P>0.3) when adjusted with blood pressure.
Conclusions— Our findings suggest that type IIb dyslipidemia has deleterious effects on vasculature already since childhood. Subjects with type IIb dyslipidemia are more vulnerable to the effects of cardiovascular risk factors and metabolic syndrome.
Dyslipidemias are the major cause for atherosclerosis. In the present study, we examined the effects of dyslipidemias from childhood to adulthood and their interaction with nonlipid risk factors on markers of subclinical atherosclerosis. Our findings suggest that type IIb dyslipidemia has deleterious effects on vasculature already since childhood.
Key Words: dyslipidemia • subclinical atherosclerosis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Dyslipidemias are the major cause for atherosclerotic diseases.1 Especially, the combination of increased concentrations of LDL-cholesterol and triglycerides, known as type IIb dyslipidemia according to Fredrickson classification,2 and its familial form familial combined hyperlipidemia (FCH), have been shown to increase the risk of cardiovascular disease. FCH affects 0.5% to 2% of the population and up to 20% of survivors of premature myocardial infarction.3,4 The mechanisms how increased cardiovascular risk associated with FCH/type IIb dyslipidemia is mediated are not completely understood. Evidence exists suggesting that part of the atherosclerotic risk associated with type IIb dyslipidemia is mediated by synergism with nonlipid risk factors and the components of the metabolic syndrome. Hopkins et al5 recently showed that the metabolic syndrome was more common in FCH families, and this increased prevalence of the metabolic syndrome alone could account for the increased coronary heart disease (CHD) risk among the family members.
Atherosclerosis begins in early life, and exposure to elevated LDL-cholesterol concentration in childhood and adolescence induce changes in arteries that contribute to the development of atherosclerosis.6–8 At present, however, there are no direct data linking childhood/early adulthood dyslipidemias to cardiovascular disease end points. As an alternative, the ultrasound measures of structural and functional changes in carotid and brachial arteries have been used as surrogate markers of cardiovascular health.9,10 Therefore, the aim of the present analysis was to examine in detail the effects of dyslipidemia phenotypes, including combined dyslipidemia, on risk of subclinical atherosclerosis in young adults, as there has been interest in early screening for lipid disorders in an attempt to identify those at high-risk for cardiovascular disease later in life. To this end, we have examined the associations of different dyslipidemia phenotypes with carotid intima-media thickness (IMT), elasticity, and brachial flow-mediated dilatation (FMD) in the Cardiovascular Risk in Young Finns Study among 2265 men and women aged 3 to 18 years at baseline (in 1980). The phenotyping was performed using longitudinal data on serum lipids during several follow-up studies between 1980 and 2001. In addition, we examined whether dyslipidemic subjects are more vulnerable to the effects of metabolic syndrome and major nonlipid cardiovascular risk factors.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The Cardiovascular Risk in Young Finns Study is an ongoing epidemiological study of atherosclerosis risk factors from childhood to adulthood. In 1980, altogether 4320 children and adolescents aged 3, 6, 9, 12, 15, and 18 years (born in 1977, 1974, 1971, 1968, 1965, and 1962) were invited to participate in the first cross-sectional study—a total of 3596 (83.2%) subjects participated. The study was carried out in all 5 Finnish university cities with medical schools (Helsinki, Kuopio, Oulu, Tampere, Turku) and their rural surroundings. Study subjects were randomly chosen from national population register from these areas. Subjects gave written informed consent in 2001, and their parents gave it in 1980. The study was approved by local ethics committees. Details of the study design have been presented elsewhere.11
The follow-up-studies were performed for the whole study group in 1983 and 1986, when 2991 (83.2%) and 2799 (78.3%) subjects participated. The 21-year follow-up was conducted in all 5 centers between September 2001 and January 2002, when 2283 subjects from the original study cohort, ie, 63.5%, participated in the study.
Lipid Measurements
Venous blood samples were drawn after an overnight fast. All lipid and lipoprotein determinations were performed on serum using standard methods, as described previously.12,13 The concentration of LDL-cholesterol was calculated using the Friedewald-formula.14 In 2001, 35 subjects had triglyceride values 
4 mmol/L preventing reliable use of the Friedewald formula. Therefore, in these subjects, LDL-cholesterol was measured by a direct homogenous LDL-cholesterol assay (LDL-C plus 2nd generation reagent, Roche Diagnostics) on a clinical chemistry analyzer (AU400, Olympus Diagnostica). Because of differences in determination methods and kits between this method and LDL-cholesterol levels calculated using Friedewald-formula, the LDL-cholesterol levels derived from the direct LDL assay were corrected by following correction factor equation determined with linear regression analysis using standardized principal component adjustments: LDL-cholesterol= 0.9645xdirect LDL-cholesterol+0.6177 mmol/L.
Clinical Characteristics and Risk Factors
Clinical characteristics were studied as follows. Height and weight were measured, and body mass index (BMI) was calculated. Blood pressure was measured using a standard mercury sphygmomanometer in 1980, and random zero sphygmomanometer in 2001. Average of 3 measurements was used in the analysis. Smoking habits and family history of CHD were inquired with a questionnaire.15 Family history was considered positive if either study subjects’ father or mother had been diagnosed with CHD, suffered from myocardial infarction, or if either of them have had percutaneous coronary intervention or coronary bypass surgery at or before the age of 55 years. Data on diabetes was assessed by questionnaire. Subjects with self reported diabetes and those with fasting plasma glucose 7.0 mmol/L were considered having diabetes.
High-sensitive C-reactive protein (CRP) concentrations were analyzed by latex turbidometric immunoassay, glucose concentrations enzymatically, and homocysteine concentrations with microparticle enzyme immunoassay kit. Details of the methods have been presented elsewhere.8,13
The metabolic syndrome was identified by the updated NCEP definition when 3 or more of the following conditions were present: waist 102 cm in men and 88 cm in women, serum triglycerides 1.695 mmol/L, HDL cholesterol <1.036 mmol/L in men and <1.295 mmol/L in women, blood pressure 130 or 85 mm Hg or treatment for hypertension, and plasma glucose 5.6 mmol/L.16
Carotid IMT
The left carotid artery was scanned by ultrasound technicians following a similar standardized protocol in 5 study centers. The image was focused on the posterior (far) wall, and gain settings were used to optimize image quality. A resolution box function (zoom) was used to record an image of 25 mm in width and 15 mm height. A magnified image was recorded from the angle showing the greatest distance between the lumen-intima interface and the media-adventitia interface. A moving scan with a duration of 5 seconds which included the beginning of the carotid bifurcation and the common carotid artery was recorded and stored in digital format on optical discs for subsequent off-line analysis.
The digitally stored scans were manually analyzed by 1 experienced reader blinded to the subjects’ details. The analyses were performed using ultrasonic calipers. From the 5-second clip image, the best quality end-diastolic frame was selected (incident with the R-wave on a continuously recorded ECG). From this image, at least 5 measurements of the common carotid far wall were taken approximately 10 mm proximal to the bifurcation to derive mean carotid IMT. To assess intraindividual reproducibility of IMT measurements, 57 subjects were reexamined 3 months after the initial visit (2.5% random sample). These scans were measured twice by the same reader to assess intraobserver reproducibility. The between-visit coefficient of variation (CV) of IMT measurements was 6.4% and the intraobserver CV was 3.4%.
Carotid Elasticity
From the 5-second clip images, the best quality cardiac cycle was selected. The carotid diameter was measured at least twice in end-diastole and end-systole, respectively. Blood pressure was measured during the ultrasound study with an automated sphygmomanometer (Omron M4, Omron Matsusaka Co Ltd). Ultrasound and concomitant brachial blood pressure measurements were used to calculate carotid artery compliance (CAC)=([Ds–Dd]/Dd)/(Ps–Pd), where Dd is the diastolic diameter; Ds, the systolic diameter; Ps, systolic blood pressure, and Pd, diastolic blood pressure. The between-visit coefficient of variation was 2.7% for carotid artery diastolic diameter and 16.3% for CAC.17
Brachial FMD
Brachial artery ultrasound studies were performed successfully for 2109 subjects.18 To assess brachial FMD, the left brachial artery diameter was measured both at rest and during reactive hyperemia. Increased flow was induced by inflation of a pneumatic tourniquet placed around the forearm to a pressure of 250 mm Hg for 4.5 minutes, followed by a release.19 Three measurements of arterial diameter were performed at end-diastole at a fixed distance from an anatomic marker at rest and 40, 60, and 80 seconds after cuff release. The vessel diameter in scans after reactive hyperemia was expressed as the percentage relative to resting scan. The average of 3 measurements at each time point was used to derive the maximum FMD. The between-visit CV for brachial diameter was 3.2% and for FMD 26.0%.18
Statistical Methods
To phenotype type IIa, IIb, and IV dyslipidemias and hypoHDL-cholesterolemia, we first calculated age and sex-specific z scores for LDL-cholesterol, HDL-cholesterol, and triglyceride values in 1980, 1983, 1986, and 2001. Then, we assessed the mean z score value (using 2 to 4 z score values per subject for each variable). Subjects with mean z score over 90th percentile for LDL-cholesterol or triglycerides were considered having type IIa or IV dyslipidemia. Subjects with mean z score over 90th percentile for LDL-cholesterol and triglycerides had type IIb dyslipidemia, and those with mean z score below 10th percentile for HDL-cholesterol had hypoHDL-cholesterolemia.
Group comparisons between nondyslipidemic subjects and those with certain dyslipidemia were performed using t tests for continuous variables and 
2-tests for categorical variables with Bonferroni correction attributable to multiple testing. To study, whether nonlipid risk factors for CHD have different influence on markers of subclinical atherosclerosis in nondyslipidemic and dyslipidemic subjects, we first calculated a nonlipid risk score. Risk factors were defined as systolic blood pressure 130 mm Hg or diastolic blood pressure 85 mm Hg, diabetes, cigarette smoking, and positive family history of CHD. Thereafter, we examined with linear regression model, whether there are significant risk scorexdyslipidemia interactions in association with ultrasound variable between dyslipidemic and control subjects. Similarly, we studied the association between metabolic syndrome and ultrasound variables.
Values for triglycerides, insulin, and C-reactive protein were log-transformed before analyses because of skewed distributions. The statistical tests were performed with Statistical Analysis System version 8.1, and statistical significance was inferred at a 2-tailed probability value of 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clinical characteristics of study subjects according to dyslipidemia phenotypes are shown in the Table. In adulthood, subjects with type IIb or type IV dyslipidemia had higher blood pressure, BMI, insulin, and CRP levels, and increased prevalence of the metabolic syndrome compared to nondyslipidemic subjects. Type IV dyslipidemia was also characterized by higher glucose levels and higher prevalence of diabetes. In type IIa subjects, the prevalence of positive family history of CHD was increased. HypoHDL-cholesterolemia was associated with increased prevalence of the metabolic syndrome. In childhood, type IIb subjects had increased BMI, and type IV subjects had increased BMI and systolic blood pressure.
|
Life-Time Dyslipidemias and Markers of Subclinical Atherosclerosis
Carotid IMT was increased in type IIb dyslipidemia (Table). The difference between nondyslipidemic subjects and those with type IIb dyslipidemia in IMT remained significant in multivariable analysis adjusted for sex, age, carotid diameter, blood pressure, BMI, CRP, homocysteine, insulin, glucose, family history of CHD, and smoking (adjusted IMTs [mean±SEM] 0.579±0.002 versus 0.607±0.022 mm, P=0.03).
Carotid compliance was decreased in type IIb and type IV dyslipidemia (Table). These differences between dyslipidemic and nondyslipidemic subjects became nonsignificant when adjusted for age, sex, and blood pressure levels. In brachial FMD, there were no differences between dyslipidemic and nondyslipidemic subjects (Table).
Early-Onset Dyslipidemias and Markers of Subclinical Atherosclerosis
We also examined the relations between dyslipidemia phenotypes and ultrasound markers using only lipid data from childhood/adolescence (study years 1980 to 1986) in classifying dyslipidemias. In these analyses, IMT was increased in type IIb (0.624 versus 0.579 mm, P=0.006, after age, sex, and risk factor adjustment P=0.02), whereas CAC was decreased only in univariate analysis (1.98%/mm Hg versus 2.20%/mm Hg, P=0.04, in multivariable model P=0.61).
Use of Quintile Cut Points in Dyslipidemia Definitions
The data were also reanalyzed using 80th and 20th percentile points (lifetime data). In these analyses, type IIb subjects had increased IMT (0.602 versus 0.578 mm, P=0.01) and decreased CAC (1.98 versus 2.22%/10 mm Hg, P=0.001) compared to controls. In multivariable analyses adjusted with age, sex, and risk factors, the difference in IMT was significant (P=0.05), whereas the difference in CAC became nonsignificant (P=0.09). In addition, when using quintile cut points in childhood/adolescence data (study years 1980 to 1986), type IIb subjects had increased IMT (0.605 versus 0.578 mm, P<0.001, in multivariable analysis P=0.006).
Effects of Nonlipid Risk Factors and Metabolic Syndrome on Carotid IMT in Type IIb Dyslipidemic and Control Subjects
To examine the possible mechanisms explaining increased IMT in type IIb dyslipidemia, we studied whether dyslipidemic subjects are more prone to the effects of other cardiovascular risk factors. The relations between IMT and the number of major nonlipid risk factors (smoking, elevated blood pressure, diabetes, and positive family history of CHD) in controls and subjects with type IIb dyslipidemia are shown in Figure 1. The association between IMT and the number of risk factors was stronger in those with type IIb dyslipidemia than in controls. Similarly, the association between IMT and the metabolic syndrome was stronger in subjects with type IIb dyslipidemia (Figure 2).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We observed that type IIb dyslipidemia is related with increased carotid IMT in young healthy adults. In addition, subjects with type IIb dyslipidemia were more prone to the atherogenic effects of nonlipid cardiovascular risk factors and metabolic syndrome than nondyslipidemic subjects.
Our results concerning IMT are in line with previous studies, which have shown that subjects with type IIb dyslipidemia or FCH have increased carotid IMT.20–23 The present findings extend prior knowledge and suggest that the harmful atherogenic effects of type IIb dyslipidemia begin already in childhood/adolescence. The subjects with type IIb dyslipidemia had 0.043 mm thicker IMTs than controls. We have recently shown that in this cohort IMT increases by 0.0057 mm per year.24 Therefore, it can be estimated that there is about 7 years difference in the vascular age25 between subjects with type IIb dyslipidemia compared to normal controls.
The prior reports on association between dyslipidemias and endothelial function have been controversial. We have previously shown in a case-control study that abnormalities in coronary flow regulation exist in young FCH patients expressing phenotype IIb.26 In smaller studies, FCH has been associated with impaired brachial FMD,27,28 but in a recent report from a larger cohort (98 FCH patients, 230 unaffected relatives, mean age approximately 50 years), there was no difference in FMD between patients and controls.29 Similarly, in the present study type IIb or other dyslipidemias were not associated with impaired brachial FMD. In another functional marker of subclinical atheroclerosis, carotid elasticity, we observed that subjects with type IIb or type IV dyslipidemia had impaired responses, but these were attributable to differences in blood pressure values between groups. The discrepancies in the associations between type IIb dyslipidemia and structural (IMT) versus functional markers of atherosclerosis (FMD, elasticity) may be partly explained by higher intraindividual variabilities in the measurements of functional markers. It is also possible that different pathophysiological mechanisms are responsible for structural and functional changes in arteries.
In the present study cohort, the deleterious effects of nonlipid risk factors and metabolic syndrome on vasculature were more pronounced among subjects with type IIb dyslipidemia. Large population-based risk factor studies, such as the Multiple Risk Factor Intervention Trial30 and the Framingham study,31 have shown that CHD risk factors act synergistically. In addition, in a study by Hopkins et al5 it was shown that increased CAD risk associated with FCH could be explained by increased prevalence of the metabolic syndrome. Our findings suggest that the synergism of cardiovascular risk factors starts already in childhood/early adulthood. Therefore, identification of young subjects with increased levels of cardiovascular risk factors would be important. We and others have shown that LDL-cholesterol values in children and adolescents can be effectively and safely lowered by lifestyle intervention.32–34 The reduction in LDL-cholesterol levels achieved by lifestyle intervention has also been associated with improved endothelial function in healthy children.35 Thus, at present there is little doubt about the safety of lifestyle modification for young individuals to maintain recommended serum lipoprotein levels, avoid smoking, and maintain a normal body weight to reduce cardiovascular risk. In line, we have previously shown in the Young Finns cohort that body mass index measured in childhood/adolescence strongly predicts body mass index in adulthood (with a 21-year tracking correlation of r=0.39).36 Moreover, in the present study, type IIb subjects did not have an increased frequency of familial history of early-onset coronary disease. Instead, they had high prevalence of increased BMI and metabolic syndrome pointing to lifestyle rather than genetic influences as main determinants of the atherogenic IIb phenotype.
Study Limitations
We do not have data on lipid values of study subjects’ family members. Therefore, we cannot study the associations between familial dyslipidemias and early atherosclerosis. As our study cohort is comprised of young adults without clinical atherosclerotic diseases, we are not able to study associations between risk factors and cardiovascular events. Instead, we have used vascular ultrasound measures as indicators of an atherogenic process. The number of subjects with type IIb dyslipidemia using the decile cut points was quite small. This might affect the statistical power of the present analyses, and especially the negative findings should be interpreted with caution. However, the relations to vascular markers remained essentially similar if less strict quintile cut points were used to define dyslipidemias. Finally, we have not genotyped the study subjects for LDL-receptor defects.
Conclusions
Our findings suggest that type IIb dyslipidemia has deleterious effects on vasculature already since childhood/adolescence. In addition, subjects with type IIb dyslipidemia are more vulnerable to the effects of cardiovascular risk factors and metabolic syndrome.
|
Acknowledgments |
|---|
Sources of Funding
This study was financially supported by the Academy of Finland (grants no. 77841, 210283, 121584, and 34316), the Social Insurance Institution of Finland, the Turku University Foundation, the Juho Vainio Foundation, Research funds from the Turku University Hospital, the Research foundation of Orion Corporation, the Finnish Medical Foundation and the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Finnish Foundation for Cardiovascular Research.
Disclosures
None.
|
Footnotes |
|---|
Original received November 27, 2007; final version accepted February 14, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med. 1984; 76: 4–12.[CrossRef][Medline] [Order article via Infotrieve]
2. Fredrickson DS, Lees RS. A system for phenotyping hyperlipoproteinemia. Circulation. 1965; 31: 321–327.
3. Goldstein JL, Hazzrad WR, Schrott HG, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest. 1973; 52: 1533–1543.[Medline] [Order article via Infotrieve]
4. Nikkilä EA, Aro A. Family study of serum lipids and lipoproteins in coronary heart-disease. Lancet. 1973; 1: 954–959.[Medline] [Order article via Infotrieve]
5. Hopkins PN, Heiss G, Ellison RC, Province MA, Pankow JS, Eckfeldt JH, Hunt SC. Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study. Circulation. 2003; 108: 519–523.
6. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation. 2001; 104: 2815–2819.
7. Li S, Chen W, Srinivasan SR, Bond MG, Tang R, Urbina EM, Berenson GS. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA. 2003; 290: 2271–2276.
8. Raitakari OT, Juonala M, Kähönen M, Taittonen L, Laitinen T, Mäki-Torkko N, Järvisalo MJ, Uhari M, Jokinen E, Rönnemaa T, Åkerblom HK, Viikari JSA. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood - The Cardiovascular Risk in Young Finns Study. JAMA. 2003; 290: 2277–2283.
9. Mancini GB, Dahlöf B, Diez J. Surrogate markers for cardiovascular disease: structural markers. Review. Circulation. 2004; 109: IV22–IV30.[Medline] [Order article via Infotrieve]
10. Cohn JN, Quyyumi AA, Hollenberg NK, Jamerson KA. Surrogate markers for cardiovascular disease: functional markers. Review. Circulation. 2004; 109: IV31–IV46.[Medline] [Order article via Infotrieve]
11. Åkerblom HK, Viikari J, Uhari M, Räsänen L, Byckling T, Louhivuori K, Pesonen E, Suoninen P, Pietikäinen M, Lähde PL, Dahl M, Aromaa A, Sarna S, Pyörälä K. Atherosclerosis precursors in Finnish children and adolescents. I. General description of the cross-sectional study of 1980, and an account of the children’s and families’ state of health. Acta Paediatr Scand Suppl. 1985; 318: 49–63.[Medline] [Order article via Infotrieve]
12. Porkka KV, Raitakari OT, Leino A, Laitinen S, Räsänen L, Rönnemaa T, Marniemi J, Lehtimäki T, Taimela S, Dahl M, Uhari M, Åkerblom HK, Viikari JS. Trends in serum lipid levels during 1980–1992 in children and young adults. The Cardiovascular Risk in Young Finns Study. Am J Epidemiol. 1997; 146: 64–77.
13. Juonala M, Viikari JSA, Hutri-Kähönen N, Pietikäinen M, Jokinen E, Taittonen L, Marniemi J, Rönnemaa T, Raitakari OT. The 21-year follow-up of the Cardiovascular Risk in Young Finns Study: risk factor levels, secular trends and east-west difference. J Intern Med. 2004; 255: 457–468.[CrossRef][Medline] [Order article via Infotrieve]
14. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18: 499–502.[Abstract]
15. Juonala M, Viikari JSA, Räsänen L, Helenius H, Pietikäinen M, Raitakari OT. Young adults with family history of coronary heart disease have increased arterial vulnerability to metabolic risk factors. The Cardiovascular Risk in Young Finns Study. Arterioscler Thromb Vasc Biol. 2006; 26: 1376–1382.
16. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eda S, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005; 112: 2735–2752.
17. Juonala M, Järvisalo MJ, Mäki-Torkko N, Kähönen M, Viikari JSA, Raitakari OT. Risk factors identified in childhood and decreased carotid artery elasticity in adulthood. The Cardiovascular Risk in Young Finns Study. Circulation. 2005; 112: 1489–1496.
18. Juonala M, Viikari JSA, Laitinen T, Marniemi J, Helenius H, Rönnemaa T, Raitakari OT. Interrelations between brachial endothelial function and carotid intima-media thickness in young adults. The Cardiovascular Risk in Young Finns Study. Circulation. 2004; 110: 2918–2923.
19. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992; 340: 1111–1115.[CrossRef][Medline] [Order article via Infotrieve]
20. Irace C, Pujia A, Motti C, Massimo F, Gnasso A. Carotid atherosclerosis in subjects with different hyperlipidaemia phenotypes. Int Angiol. 1998; 17: 15–21.[Medline] [Order article via Infotrieve]
21. Keulen ET, Kruijshoop M, Schaper NC, Hoeks AP, de Bruin TW. Increased intima-media thickness in familial combined hyperlipidemia associated with apolipoprotein B. Arterioscler Thromb Vasc Biol. 2002; 22: 283–288.
22. ter Avest E, Holewjin S, Bredie SJ, Stalenhoef AF, de Graaf J. Remnant particles are the major determinant of an increased intima media thickness in patients with familial combined hyperlipidemia (FCH). Atherosclerosis. 2007; 191: 220–226.[CrossRef][Medline] [Order article via Infotrieve]
23. Junyent M, Zambon D, Gilabert R, Cofan M, Nunez I, Ros E. Carotid atherosclerosis in familial combined hyperlipidemia associated with the APOB/APOA-I ratio. Atherosclerosis. In press.
24. Juonala M, Kähönen M, Laitinen T, Hutri-Kähönen N, Jokinen E, Taittonen L, Pietikäinen M, Helenius H, Viikari JS, Raitakari OT. 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. In press.
25. Stein JH. Carotid intima-media thickness and vascular age: you are only as old as your arteries look. J Am Soc Echocardiogr. 2004; 17: 686–689.[CrossRef][Medline] [Order article via Infotrieve]
26. Pitkänen OP, Nuutila P, Raitakari OT, Porkka K, Iida H, Nuotio I, Rönnemaa T, Viikari J, Taskinen MR, Ehnholm C, Knuuti J. Coronary flow reserve in young men with familial combined hyperlipidemia. Circulation. 1999; 99: 1678–1684.
27. Karasek D, Vaverkova H, Halenka M, Budikova M, Novoty D. Brachial endothelial function in subjects with familial combined hyperlipidemia and its relationships to carotid artery intima-media thickness. Int Angiol. 2006; 25: 418–426.[Medline] [Order article via Infotrieve]
28. De Michele M, Iannuzzi A, Salvato A, Pauciullo P, Gentile M, Iannuzzo G, Panico S, Pujia A, Bond GM, Rubba P. Impaired endothelium-dependent vascular reactivity in patients with familial combined hyperlipidemia. Heart. 2007; 93: 78–81.
29. ter Avest E, Holewjin S, van Tits LJ, de Wit HM, Stalenhoef AF, de Graaf J. Endothelial function in familial combined hyperlipidaemia. Eur J Clin Invest. 2007; 37: 381–389.[CrossRef][Medline] [Order article via Infotrieve]
30. Kannel WB, Neaton JD, Wentworth D, Thomas HE, Stamler J, Hulley SB, Kjelsberg MO. Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Multiple Risk Factor Intervention Trial. Am Heart J. 1986; 112: 825–836.[CrossRef][Medline] [Order article via Infotrieve]
31. Wilson PW, Castelli WP, Kannel WB. Coronary risk prediction in adults (the Framingham Heart Study). Am J Cardiol. 1987; 59: 91G–94G.[CrossRef][Medline] [Order article via Infotrieve]
32. Lapinleimu H, Viikari J, Jokinen E, Salo P, Routi T, Leino A, Rönnemaa T, Seppänen R, Välimäki I, Simell O. Prospective randomized trial in 1062 infants of diet low in saturated fat and cholesterol. Lancet. 1995; 345: 471–476.[CrossRef][Medline] [Order article via Infotrieve]
33. Obarzanek E, Kimm SY, Barton BA, Van Horn LL, Kwiterovich PO Jr, Simons-Morton DG, Hunsberger SA, Lasser NL, Robson AM, Franklin FA Jr, Lauer RM, Stevens VJ, Friedman LA, Dorgan JF, Greenlick MR. Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC). Pediatrics. 2001; 107: 256–264.
34. Kaitosaari T, Rönnemaa T, Raitakari O, Talvia S, Kallio K, Volanen I, Leino A, Jokinen E, Välimäki I, Viikari J, Simell O. 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. Circulation. 2003; 108: 672–677.
35. Raitakari OT, Rönnemaa T, Järvisalo MJ, Kaitosaari T, Volanen I, Kallio K, Lagström H, Jokinen E, Niinikoski H, Viikari JS, Simell O. 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). Circulation. 2005; 112: 3786–3794.
36. Juonala M, Viikari JSA, Rönnemaa T, Taittonen L, Marniemi J, Raitakari OT. Childhood C-reactive protein in predicting CRP and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. Arterioscler Thromb Vasc Biol. 2006; 26: 1883–1888.
This article has been cited by other articles:
 |
|
 |
|
  P. O. Kwiterovich Jr. Recognition and Management of Dyslipidemia in Children and Adolescents J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4200 - 4209. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||