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Detection of Early Atherosclerosis Using the Ultrasound Parameter of the Intima-Media Thickness of the Common Carotid Artery in Families With Familial Combined Hyperlipidemia

Posted on: Sunday, 23 January 2005, 03:00 CST

Aim. The aim of the present study was to quantify intimamedia thickness (IMT) of the common carotid artery (CCA) in clinically asymptomatic members of familial combined hyperlipidemia (FCHL) families and to evaluate its association with lipids, apoproteins, blood pressure, surrogate markers of insulin resistance, fibrinogen and hs-CRP.

Methods. The group under study consisted of 82 individuals from 29 FCHL families (47 hyperlipidemic [HL] and 35 normolipidemic [NL]). They were compared with the age and sex adjusted control groups of healthy subjects (HL-c, n=20 and NL-c, n=20). IMT was measured by ultrasound at a far wall of both common carotid arteries.

Results. Hyperlipidemic subjects had increased IMT compared with healthy controls (0.6950.118 vs 0.5990.074 mm), with an age and sex corrected difference of 86 mm (p<0.001). No difference in IMT was recorded in NL FCHL members in comparison with their healthy controls. In HL subjects, significantly positive univariate correlations were observed between IMT and age, total cholesterol, LDL-cholesterol, non-HDL-cholesterol, apolipoprotein B, SBP, DBP, BMI, waist, fasting glycemia, C-peptide and proinsulin, whereas in NL subjects IMT correlated only with age. Multivariate regression analysis in FCHL subjects (HL+NL) revealed that age (p<0.001), sex (p<0.001), non-HDL-cholesterol (p<0.01) and BMI (p<0.05) were significant and independent predictors of IMT.

Conclusion. The increase of IMT CCA in hyperlipidemic still clinically asymptomatic FCHL subjects corresponds to acceleration of the clinically "silent" atherosclerosis by about 8-14 years and is in agreement with their increased risk of atherosclerosis.

[Int Angiol 2004;23:230-7]

Key words: Atherosclerosis - Intima-media thickness - Familial combined hyperlipidemia - Risk factors -Atherosclerosis.

Familial combined hyperlipidemia (FCHL), the most common genetic dysplipidemia, characterized by multiple lipoprotein pheiiotypes and an increased risk of premature coronary artery disease (CAD),1-5 affects 0.5-2% of the populations.1,2 Lipid changes are the result of the overproduction of apolipoprotein B (apoB) containing very low density (VLDL) lipoproteins and impaired clearance of postprandial lipoproteins.6,7 Concentrations of total cholesterol (TC) and cholesterol of low density lipoproteins (LDL-C) are mostly lower than in familial hypercholesterolemia and lipid abnormalities are fully expressed later, usually at the age of 30 years. Despite this fact, FCHL is associated with premature manifestation of atherosclerosis.1 5 This may be due to other quantitative and qualitative changes in lipoprotein metabolism like the presence of small dense LDL, increased triglyceride-rich lipoproteins and their remnants, prolonged postprandial lipemia, impaired metabolism of free fatty acids, decreased level of high density lipoproteins (HDL) and decreased activity of lipoprotein lipase or increased levels of its inhibitor, apolipoprotein C-III.6-9 A frequent presence of insulin resistance with impaired glucose homeostasis 10 and hypertension n may also play a role in premature development of atherosclerosis. Various phenotypic expression of FCHL makes difficulties in diagnosis of this disorder.12

In patients with premature myocardial infarction (by less than 60 years of the age), this dyslipidemia was diagnosed in 10-20% of cases.1-3 In FCHL families an enhanced risk of fatal (1.7 fold) and non-fatal myocardial infarction (5.1 fold) was proved.4,5 Frequent occurrence of FCHL was recorded also in families of patients after premature cerebrovascular accident.13,14

The intima-media thickness (IMT) of the common carotid artery (CCA) is a recognized morphological marker of early atherosclerosis. IMT reflects integrally the effect of individual risk factors of atherosclerosis and some intervention measures performed to eliminate the effect of these risk factors.15,17 Moreover, IMT represents the ultrasound parameter with a good predictive value on the generalized status of atherosclerosis of coronary,18, 20 cerebral21-22 and lower extremity arteries.23, 24 IMT also predicts progression of atherosclerotic complications in these localizations.20,25 The ultrasound measurement of the IMT CCA complex is advantageous for its non-invasive character, availability and reproducibility, providing qualitative information about the involvement of the vascular wall.

The aim of this study was to assess the presence of subclinical atherosclerosis in clinically asymptomatic members of FCHL families compared with healthy control subjects using the measurement of IMT CCA complex. In addition to that, relationship between IMT and various risk factors of atherosclerosis (lipids, lipoproteins, apoproteins, blood pressure, surrogate markers of insulin resistance and inflammatory parameters hs-CRP and fibrinogen) was investigated.

Materials and methods

The study was carried out with 82 subjects from 29 FCHL families, who had been examined in the Lipid Center of the 3rd Clinic of Internal Medicine, University Hospital, Olomouc, Czech Republic. A FCHL family was diagnosed according to the following criteria: probands with the level of both total cholesterol (TC) and triglycerides (TG) ≥90th percentile for a given age and sex of the Czech population (based on the data of population study MONICA,26 Table I). At least one Ist-degree relative of the proband should have the level of TC and/or TG ≥90th percentile of a given age and sex or apoB ≥1.25 g/L.27,28 At the same time, secondary or another primary hyperlipoproteinemia (the presence of apoE2/E2 genotype or the clinical diagnosis of familial hypercholesterolemia) was excluded in those subjects. Other exclusion criteria were as follows: history of the clinically manifested atherosclerosis (coronary artery disease, heart failure, cerebrovascular accident, reversible ischemic neurological deficit and transitory ischemic attack, peripheral vascular disease), smoking, diabetes mellitus, previous hypolipidemic therapy, hormone therapy with estrogens and clinical presence of acute infectious disease or trauma. Hypertensive subjects were not excluded because hypertension is a common feature in FCHL. FCHL subjects were divided into 2 groups. The hyperlipidemic group (HL, n=47, 27 men) comprised the probands and their first-degree relatives, who had TC and/or TG ≥90th percentile or apoB ≥1.25 g/L, i.e. they had a manifested FCHL. The group of FCHL-non-affected normolipidemic subjects (NL, n=35, 11 men) comprised the firstdegree relatives of probands who did not meet the above-mentioned criteria. The age- and sexmatched control groups were comprised in the study: the HL-c group (n=20, 12 men) matched to the HL group and NL-c (n=20, 6 men) to the NL group. Control groups consisted of healthy individuals with negative family history of hyperlipidemia and early manifestation of atherosclerosis.

Ultrasound scanning was performed with a 10 MHz linear array transducer (Hewlett-Packard Image Point M2410A), All measurements were performed with the subjects in a supine position. The head was tilted to the contralateral side at the angle of 45. The longitudinal B-mode image of CCA just before the widening of the bulb was displayed. When an optimal longitudinal image of far wall of ACC in the region of 1 cm proximally from the bulb was obtained, it was frozen on the R wave according to a simultaneous ECG and videotaped (Panasonic VCR AG-MD 830, S-VHS videocassette). Three video records were made on both ACC. IMT measurements were processed offline using the software Image-Pro Plus (Version 4.0, Media- Cybernetics, Silver Springs, USA). The region under evaluation was the CCA wall 1-2 cm distant proximally from the mentioned border. The average of all mean IMT CCA of 3 frozen images of both sides was chosen as the outcome variable. Ultrasound examinations and measurements of IMT were made by 2 physicians. Subjects with a present atherosclerotic plaque in the evaluated region were not included in the study.

TABLE I.-Values of 90th percentiles of the Czech population for total cholesterol and triglycerides in men and women in individual age categories (Czech post-MONICA study, kindly provided by doc. MUDr. R. Ciflcova, IKEM, Prague).26

TABLE II.-Basic characteristics in individual groups.

As IMT CCA was registered and evaluated independently by 2 physicians, the inter- and intraindividual variability of ultrasound measurements was evaluated in 22 healthy subjects (12 women, 10 men, mean age of 35.27.8 years), who were examined repeatedly at the interval of 1 month. Mean differences were for left IMT CCA 0.030.027 mm, rightIMT CCA 0.030.021 mm and mean IMT 0.0320.021 mm. Variation coefficients were for left IMT CCA 2.18%, for right IMT CCA 2.05% and for mean IMT 1.72%. The measurement of IMT was made without knowledge of laboratory results.

TC and TG were determined by enzyme methods CHOD-PAP and GPO- PAP. Determination of HDL-C was made by a direct method without precipitation of apoB containing lipoproteins. The value of LDL-CH was calculated automatically using Friedewald formula (to TG value <4.5 mmol/L, not calculated in 6 hypertriglyceridemic subjects). Non- HDL-cholesterol was calculated as a difference b\etween TC and HDL- C. From levels of TG and HDL-C was calculated the socalled atherogenic index (AI=log [TG/HDL-C]). Concentration of apoB was determined immunoturbidimetrically using specific antibodies (Tinaquant Apolipoprotein B, Roche, Basel, Switzerland). Hs-CRP was determined by means of an ultrasensitive immunoturbidimetric method on the kit Tina-quant (Roche, Basel, Switzerland). All the above- mentioned examinations were made on a full-automated analyzer Hitachi 917 (Roche, Basel, Switzerland). The material examined was fresh serum. Fibrinogen concentration determined by the test IL TestTM Fibrinogen-C kits (Instrumentation Laboratory, Milan, Italy) using the method according to Clauss on Automated Coagulation Laboratory analyzers. Fibrinogen was determined directly from fresh plasma. Glycemia was determined on the kit Glucose GOD-PAP by enzyme method. Fasting insulin and C-peptide were determined on the commercially available kits Insuline and C-peptide (Immunotech, Marseille, France) using specific antibodies by IRMA method. The parameter of insulin resistance HOMA (homeostasis model assessment) was calculated according to the equation: HOMA=fasting glycemia*fasting insulinemia/22.5). Of clinical parameters, systolic (SBP) and diastolic blood pressures (DBP) were measured in a standardized fashion (the mean of 3 measurements was used), body mass index (BMI) was assessed (BMI=weight in kg/height in m^sup 2^) and waist circumference was measured.

Statistical analysis

Differences between individual groups were calculated using linear regression analysis with age and sex as covariables. For statistical evaluation of dependence of IMT on selected risk factors of atherosclerosis we used the univariate correlation analysis after the preceding normality test according to Kolmogorov-Smirnov. In case of normal distribution of parameters, Pearson correlation test was used subsequently, in case of abnormal distribution (TG, hs- CRP, proinsulin, insulin, C-peptide, HOMA, SBP, DBP) we used Spearman correlation test. For testing of independent effect of some variables under study on IMT in members of FCHL families, the effects of such variable, adjusted for other independent variables, were analysed by backward stepwise multiple linear regression analysis with IMT as a dependent variable. Statistical analysis was made on the software SPSS for Windows version 12.0 (Chicago, Illinois, USA). All values given in the present paper are expressed as meanstandard deviation. Values p<0.05 were considered as statistically significant.

The Ethics Committee of Medical Faculty and University Hospital Olomouc approved the design of the study and informed consent was obtained from all participants.

Figure 1.-Extent of IMT in FCHL subgroups: HL and NL, comparison with controls HL-c, NL-c (IMT/mm/SD). p values are shown after adjustment for age and sex.

Results

Basic characteristics of individual groups are given in Table II. The HL group, compared with the control HL-c group, showed expected differences in TC, LDL-C, non-HDL-C, TG and apoB, because that group was defined on the basis of present hyperlipidemia. The HL subjects also had higher diastolic blood pressure (DBP), BMI, and of the other laboratory parameters, fibrinogen, fasting glycemia, C- peptide, proinsulin and hs-CRP. Their SBP and waist circumference were not different, as well as their laboratory values of HDL-C, fasting insulin and HOMA. The NL group, compared with the control group NL-c, showed significant differences only in the levels of TG, proinsulin and DBP.

The results obtained from measurement of IMT complex are given in Figure 1. A mean value of IMT in the HL group was 0.6950.118 mm, in the HL-c group 0.5990.074 mm. The age and sex corrected difference of 86 m between both groups was statistically significant (p<0.001). In the NL group we recorded the value of IMT 0.5540.061 mm and in the NL-c group the value 0.5480.041 mm; the found age and sex corrected difference of 5 m was of no statistical significance.

Statistical evaluation of the association between IMT and other parameters is summarized in Table III. In the whole FCHL group (HL+NL) we found a statistically significant association between IMT and age, sex, TC, LDL-C, TG, non-HDL-C, apoB, SBP, DBP, BMI, waist, AI, proinsulin, C-peptide and fibrinogen. In the group HL we recorded a statistically significant association between IMT and age, TC, waist, apoB, non-HDL-C, proinsulin, C-peptide, DBP, BMI, LDL-C and SBP In the group NL, IMT correlated significantly only with age. After aplication of the multiple backward linear regression analysis in members of FCHL families (HL+NL), the independent risk factors affecting IMT thickness were age (p<0.001), sex (p<0.001), non-HDL-C (p<0.01) and BMI (p<0.05), (Table IV).

TABLE III.-Correlation between IMT and selected risk factors of atherosclerosis and insulin resistance parameters in all FCHL family members (HL+NL) and separately in hyperlipidemic (HL) and normolipidemic subjects (NL).

TABLE IV.-Results of backward stepwise regression analysis in 82 FCHL subjets with IMT as dependent variable.

Discussion

FCHL subjects have a significantly higher cardiovascular risk and an early occurrence of CAD, despite a relatively late manifestation of hyperlipidemia. These high risk subjects should be screened early in the clinically asymptomatic period to allow aggressive intervention of all risk factors of atherosclerosis.

Detection of early clinically asymptomatic atherosclerosis using the ultrasound parameter IMT in FCHL subjects has been described only in a few papers.29-31 In agreement with the results obtained by Keulen et al., the present paper reports on significant associations between the examined lipid parameters and IMT.29

In FCHL affected subjects of Keulen et al., multivariate regression analysis revealed that age, sex and apoB were significant and independent predictors of IMT; BMI was of borderline significance. Our results were similar in age, sex, non-HDL-C, and BMI as independent predictors of IMT. ApoB is considered as the best marker of the number of all atherogenic particles, because each lipoprotein particle (VLDL, IDL, LDL, chylomicron and chylomicron- remnants) contains 1 apoB molecule. On the contrary, non-HDL-C represents cholesterol in all potentially atherogenic particles and takes into consideration also concentrations of HDL-C, which were in our FCHL members nonsignificantly lower than in control subjects. Moreover, a strong correlation between apoB and nonHDL-C has been reported.

In contrast to that, another paper by Finnish authors did not prove in FCHL families any association between IMT and lipid values by using multivariate analysis.30 However, their FCHL patients with apoB ≥1.1 g/L had significantly greater mean IMT than subjects with apoB <1.1 g/L. The next communication of the same working group reported on the association of the IMT with the size of LDL particles.31

The ultrasound measurement of IMT CCA complex showed repeatedly to be a suitable morphologically defined marker of early atherosclerosis and its generalization.25 Adequate standardization of IMT measurements and its evaluation could allow to use this parameter for improvement of defining individual CAD risk and selection of aggressiveness of individual pharmacological interventions.

The significantly increased IMT found in our study in HL subjects with FCHL corresponds to an enhanced risk of manifested cardiovascular dis ease in FCHL families.1-5 On the basis of results obtained from extensive prospective population studies, the annual "physiological" progression rate of IMT has been estimated to 6-10 m. 15>32 The age and sex corrected difference of IMT found by us in HL group compared with the control group, representing 86 m, corresponds approximately to 814 years of natural increase of IMT. The study of Keulen et al. ,29 dealing with IMT complex in FCHL subjects in a similarly structured group (mean age of 48.5 years, still clinically asymptomatic, hyperlipidemic subjects) revealed a statistically significant increase of IMT by 57 mm, which corresponds to the physiological increase of IMT by 5-9 years. A higher IMT difference recorded in our study may be explained partly by the fact that Keulen's study comprised about 40% subjects treated previously with hypolipidemic drugs prior to study. Several papers reported that therapy with various statins resulted in a lowered IMT progression or even regression.33-36

A detailed evaluation of the effect of insulin resistance on parameters under study was not the aim of the present paper. Nevertheless, it appeared to be a significant proatherogenic factor as indicated by significant univariate correlations between IMT and selected laboratory and clinical markers, typically associated with the metabolic syndrome. These associations are in accordance with the conclusions drawn by many authors, e.g. Haffner et al.37 and Shinozaki et al.38 These findings are probably due to the fact that FCHL is a clinical syndrome with significant pathogenetic involvement of insulin resistance. Atherogenic mechanisms mediated by insulin resistance are highly heterogenoussestarting with an endothelial dysfunction through the interaction with c-NOS activity up to the association with obesity, arterial hypertension, dyslipidemia and prothrombogenic state. Insulin resistance may play a significant role also in the induction of proatherogenic state in HL subjects with FCHL.

The application of the multivariate linear regression analysis showed that most markers of insulin resistance (except BMI) lost their independent predictive value and the only independent risk factors were age, sex, non-HDL-C and BMI. BMI influences many lipid parameters, as well as insulin resistance. This finding stresses the importance of normal body weight in threatened members of these families and the importance of early \nonpharmacological intervention, which is unfortunately often neglected.

Inflammation may play an important role both in atherosclerosis and insulin resistance. Levels of hs-CRP and fibrinogen were significantly higher in our HL individuals than in control subjects. However, after multivariate linear regression analysis, neither hs- CRP nor fibrinogen was independent predictors of IMT CCA.

The results obtained from IMT measurement indicated a significant difference between HL subjects and healthy controls. No statistically significant difference was found between NL FCHL subjects and age- and sex-matched controls. However, a similarly structured group of FCHL subjects in our previous study showed a statistically significant difference between NL individuals and their controls in the parameter of endothelial vasomotor function, the so-called flow-mediated dilatation of the brachial artery.39 This fact indicates that in some NL subjects other genetic factors, such as insulin resistance may be involved in the impairment of endothelial function, and hyperlipidemia may manifest subsequently. This finding supports the hypothesis on a crucial role of endothelial dysfunction in pathogenesis of early atherosclerosis, which may precede the morphologically distinct changes of vascular wall measurable by thickened IMT complex. Flow mediated dilatation of the brachial artery may be also an integral marker of the endothelium-dependent vasomotor function reflecting more sensitively and earlier than IMT the earliest stages of atherosclerosis.

Conclusions

The increase of IMT CCA in FCHL-affected subjects without clinical signs of CVD corresponds to acceleration of the still clinically "silent" atherosclerosis by about 8-14 years compared with healthy controls. The ultrasound parameter of IMT thus seems to be a promising prognostic marker of subclinical atherosclerosis in such defined individuals with high cardiovascular risk. This parameter may be of high usefulness, but first of all an adequate standardization of measurement and evaluation of results should be made. According to the last recommendation of ESC CPG (European Society of Cardiology Committee for Practice Guidelines), increased IMT CCA is considered, despite the above limitations, as the cardiovascular risk factor in asymptomatic subjects.40

This work was supported by grants WZ MSM 151100005 and IGA MH CR NB 6563-3/2001.

Received May 4, 2004 accepted for publication August 26, 2004.

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M. HALENKA1, H. VAVERKOVA 1, M. HUTYRA 2, D. KARASEK 1, L. SLAVIK 3 D. NOVOTNY 4, M. KRSKOVA 5

1 3rd Clinic of Internal Medicine, University Hospital and Medical Faculty of Palacky University, Olomouc, Czech Republic

2 1st Clinic of Internal Medicine, University Hospital and Medical Faculty of Palacky University, Olomouc, Czech Republic

3 Department of Consolidated Biochemical Laboratories, University Hospital and Medical Faculty of Palacky University, Olomouc, Czech Republic

4 Hemato-Oncologic Clinic, University Hospital and Medical Faculty of Palacky University, Olomouc, Czech Republic

5 Computer Center, University Hospital and Medical Faculty of Palacky University, Olomouc, Czech Republic

Address reprint requests to: MUDr. M. Halenka, 3rd Clinic of Internal Medicine, University Hospital, I.P. Pavlova 6, Olomouc 775 20, Czech Republic. E-mail: milan.halenka@fnol.cz

Copyright Edizioni Minerva Medica Sep 2004

Source: International Angiology

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