doi: 10.1161/hq0202.104100
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Increased Intima-Media Thickness in Familial Combined Hyperlipidemia Associated With Apolipoprotein B
From University Hospital Maastricht (E.T.P.K., M.K., N.C.S., T.W.A.d.B.), Department of Medicine, and Laboratory of Molecular Metabolism and Endocrinology, Cardiovascular Research Institute Maastricht, and University Maastricht (A.P.G.H.), Department of Biophysics, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
Reprint requests to Dr Tjerk W.A. de Bruin, MD, PhD, Department of Medicine and Endocrinology, University Hospital Maastricht, P. Debyelaan 25/PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail tdb{at}sint.azm.nl
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Abstract |
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The aim of the present study was to quantify intima-media thickness (IMT) in familial combined hyperlipidemia (FCHL) and to evaluate the relationship of IMT in FCHL-affected subjects with lipids and apolipoproteins, blood pressure values, and surrogate markers of insulin resistance. IMT was measured by ultrasound at the left and right common carotid arteries in 46 FCHL-affected subjects who were free of clinical manifestations of atherosclerosis and in 55 age- and sex-matched healthy control subjects. FCHL-affected subjects had significantly increased IMT compared with healthy control subjects, with a difference of 57 µm (age- and sex-corrected P<0.01). In the FCHL group, significantly positive age- and sex-corrected univariate correlations were observed between IMT and total cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B. Multivariate regression analyses revealed that age, sex, and apolipoprotein B were significant and independent predictors of IMT, whereas body mass index was of borderline significance. Combined, these factors explained almost 50% of the observed IMT variation (P<0.001). The increased IMT observed in FCHL corresponds with
7 years of physiological IMT increase in excess of the average IMT in age- and sex-matched control subjects. These novel findings show the important relationship between lipoprotein particles, marked by increased apolipoprotein B concentrations, and an increased IMT in FCHL. The increased IMT in FCHL-affected subjects is in agreement with the known high risk of cardiovascular disease in FCHL.
Key Words: atherosclerosis • body mass index • hypercholesterolemia • insulin resistance
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Introduction |
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Familial combined hyperlipidemia (FCHL), the most common genetic dyslipidemia in humans, affects 0.5% to 2% of the population, and 10% to 20% of survivors of premature myocardial infarction (MI) exhibit FCHL.1–3 Recently, 2 reports have shown that FCHL relatives also have a markedly increased risk of fatal and nonfatal coronary artery disease (CAD), with odds ratios of 1.7 and 5.1, respectively.4,5 However, these clinical sequelae are usually preceded by asymptomatic atherosclerotic changes in the vessel wall. Ultrasound measurement of intima-media thickness (IMT) in the carotid wall is currently used as a marker of asymptomatic atherosclerosis. Cross-sectional studies have shown an association between carotid IMT and various cardiovascular risk factors6–8 and the prevalence of CAD.9,10 Moreover, carotid IMT has been validated as a predictor of future CAD in prospective studies, independent of other cardiovascular risk factors.11,12 To our knowledge, no results of IMT measurements in an FCHL population have been published to date. Moreover, because of the strong association between FCHL and elevated apoB, IMT measurement in FCHL provides an opportunity to evaluate the relationship between apoB and IMT.
FCHL is a hyperlipidemic metabolic syndrome associated with apoB overproduction,13 relatively impaired lipoprotein elimination,14 impaired insulin-stimulated glucose uptake,15 and central obesity.16 Moreover, the prevalence of dyslipidemic hypertension in families with FCHL is increased 2-fold.16 Clearly, the aggregate of these abnormalities results in an unfavorable atherogenic risk profile in FCHL and increases the risk of enhanced atherosclerosis and subsequent cardiovascular events.
It is the objective of the present study to assess the amount of asymptomatic atherosclerosis by ultrasound carotid IMT measurement in subjects with FCHL compared with healthy control subjects and to investigate in FCHL subjects the potential relationship of IMT with lipids and lipoproteins, blood pressure values, and surrogate markers of insulin resistance.
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Methods |
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One hundred thirteen subjects participated in the present study: 58 (31 men) hyperlipidemic FCHL subjects and 55 (29 men) age- and sex-matched healthy control subjects. FCHL was diagnosed in a family according to the following criteria: (1) a primary hyperlipidemia, including fasting total plasma cholesterol (TC) >6.5 mmol/L (250 mg/dL) and/or fasting plasma triglyceride (TG) concentration >2.0 mmol/L (180 mg/dL); (2) multiple lipoprotein phenotypes within a family (Fredrickson’s classification IIa, IIb, or IV); and(3) a positive family history of premature cardiovascular disease (CVD).5,14,16 Premature CVD was defined as the occurrence of an MI or cerebrovascular accident before the age of 60 years. Individuals with secondary causes of hyperlipidemia (renal or hepatic insufficiency, hypothyroidism, and medication), the presence of the apo E2/E2 genotype, and tendon xanthomas or a diagnosis matching familial hypercholesterolemia were excluded.
Hyperlipidemic FCHL subjects (n=58) included in the present study were characterized by a primary hyperlipidemia, defined as fasting TC >6.5 mmol/L (250 mg/dL) and/or fasting plasma TG concentration >2.0 mmol/L (180 mg/dL).16 Eleven FCHL subjects had a history of previous CVD: 2 had experienced an MI, 3 had angina pectoris, 1 had undergone a coronary artery bypass graft, 3 had experienced a cerebrovascular accident, and 2 showed peripheral atherosclerotic disease. All FCHL subjects were randomly recruited from 15 large FCHL families. The average number of subjects from 1 family was 4. However, because of the lack of genetic independence in these subjects, a family dummy variable was included in the analyses. Control subjects were population-based volunteers (n=24) and spouses (n=31) from the FCHL families. All healthy control subjects had no clinical signs of CVD. The study protocol was approved by the Human Investigations Review Committee and was performed according to the Helsinki Declaration. All subjects gave written informed consent.
Measurements
The measurements were performed in the morning (8:00 to 11:00 AM) after an overnight fast (12 to 14 hours). Subjects had refrained from smoking and did not drink coffee or tea in the morning. Subjects had also abstained from alcohol for at least 72 hours. Any lipid-lowering medication had been withdrawn for 2 weeks before all measurements. A medical history was obtained from all participating subjects, and a standardized questionnaire was filled out. All patients were weighed in their underwear, height was determined by stadiometer, and the body mass index (BMI) was subsequently calculated as weight in kilograms divided by height in meters squared. The waist circumference was measured at the level of the umbilicus, the hip circumference was measured at the level of the trochanter major, and the waist-to-hip ratio was calculated. Waist circumference and hip circumference were measured with each subject in the standing position. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured twice, with an Omron 705CP (OMRON Health Care GmbH) in a standardized fashion with the subject in sitting position after 10 minutes of rest. Cuff size was adjusted to the circumference of the arm, and the arm was placed with the cuff at heart level. The mean of 2 measurements was used in the statistical analyses.
IMT Measurement
The IMT measurements were performed with an Ultramark 4+ (Advanced Technology Laboratories) with a linear array transducer of 7.5 MHz. All measurements were performed with the subjects in a supine position in a quiet room. During the measurements, the head was tilted to the contralateral side at an angle of 45°. The automated radiofrequency (RF) method used to assess IMT has been described in detail before.17 Briefly, a B-mode image was obtained from the common carotid artery in a longitudinal section just before the widening of the bulb in the bifurcation. An M line was positioned perpendicular to the posterior wall 10 to 20 mm proximal to the carotid bulb, showing a clear intima-media complex during the whole measurement. Subsequently, the ultrasound system was switched to M mode, and ECG-triggered RF data collection was started at a sample frequency of 18.4 MHz and an M-line update frequency of 800 Hz for a time period of 5 seconds, corresponding to 4 to 6 heartbeats. For each heartbeat, the amplitude distribution was evaluated to automatically detect the positions of the walls. Subsequently, the locations of the intima and the media-adventitia edge of the posterior wall were determined, and IMT was defined as the distance between both edges. The maximum ratio of the intimal to adventitial amplitude was set at 1.0 to suppress the detection of false edges. The resolution for wall thickness detection was 40 µm.17 Only the posterior wall was investigated, because there the reflections from the blood-intima and media-adventitia transition are distinctly visible, whereas at the anterior wall the trailing edge of the adventitia may obscure the medial and intimal signals. Each heartbeat within a recording resulted in an estimate of IMT. Measurements were repeated 7 times at the left and right common carotid arteries. The average of the median values for each measurement obtained on both sides was taken as a representative IMT value. The ultrasound M-mode and RF signal method to measure IMT instead of offline B-mode measurement has been validated previously.18 The intraobserver variabilities were 5.9% (E.T.P.K.) and 6.3% (M.K.), as determined in 10 subjects on 2 occasions. The interobserver variability was 4.6%, as determined in 10 subjects.
Laboratory Methods
After the completion of the IMT measurement, fasting venous blood was collected in precooled EDTA (1 mg/mL) Vacutainer tubes for measurements of lipids, lipoproteins, glucose, and insulin. TC and fasting TG concentrations were measured in duplicate by a commercially available colorimetric assay (Monotest Cholesterol kit No. 1442350 and GPO-PAP No. 701912, respectively, Boehringer-Mannheim). HDL cholesterol (HDL-C) was determined after phosphotungstate-MgCl2 precipitation of whole plasma. Fasting plasma LDL cholesterol (LDL-C) was calculated according to the Friedewald formula: LDL-C=TC-HDL-C-(TGx0.45),19 if plasma TG concentration was <4.5 mmol/L (390 mg/dL). If plasma TG was >4.5 mmol/L, LDL-C was measured in the density 1.019 to 1.063 fractions, prepared after equilibrium ultracentrifugation. Nonesterified fatty acids were measured in plasma samples by an enzymatic colorimetric method (Wako Chemicals GmbH).
Glucose (FBG) was measured immediately on a YSI 2300 monitor (Yellow Spring Instruments). Fasting insulin concentration (FI) was determined by using an ELISA (Mercodia AB), with a cross-reactivity with proinsulin <0.01%. Insulin resistance was calculated by the homeostasis model assessment (HOMA) formula: resistance=FI/(7x22.5x
-ln FBG), which can be simplified as (FIxFBG)/(7x22.5).20 Plasma apoB and apoA-1 were determined by commercially available immunonephelometric assays, with the use of calibrated standards according to the International Federation for Clinical Chemistry (Behringwerke).21
Statistical Analyses
All values are expressed as mean±SD. To obtain normal distribution, logarithmically transformed values for FI and TG concentrations were used in statistical analyses; values are nonlogarithmically listed in Table 1 for practical reasons. Differences between FCHL subjects and healthy control subjects were calculated by using linear regression analyses with age and sex as covariables.22 In the FCHL subjects as well as in healthy control subjects separately, age- and sex-corrected Pearson correlation coefficients were determined for the relationship between continuous IMT variable, plasma lipids and lipoproteins, blood pressure values, and surrogate markers of insulin resistance. To test whether variables had an independent effect on the IMT in the FCHL group, the effects of such a variable, adjusted for other independent variables, were analyzed by backward stepwise multiple linear regression analyses with IMT as an dependent variable.22 Although, as pointed out above, a family relationship was present between several FCHL subjects, the backward stepwise multiple linear regression analyses showed no significant contribution of 1 of the families to our results. In all statistical analyses, the statistical package SPSS 8.0 (SPSS Inc) was used.
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Results |
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The characteristics of the subjects studied are presented in Table 1. Compared with healthy subjects, FCHL subjects had significantly higher SBP, fasting TC, fasting TG, LDL-C, and apoB concentrations and lower HDL-C concentrations. Furthermore, FI levels and calculated HOMA values were higher in FCHL subjects than in control subjects, comparable with the known state of insulin resistance in FCHL.
The results of the IMT measurements are depicted in Table 2. Previous studies have shown that IMT increases with age and that IMT is increased in the male population compared with the female population.6,7 Therefore, IMT was corrected for age and sex by using linear regression analysis. For technical reasons, no data on IMT were available for 1 FCHL subject and 2 control subjects. Linear regression analyses showed that IMT was significantly increased in FCHL subjects compared with healthy control subjects, with a difference of 63 µm (age- and sex-corrected P<0.01). As stated above, 11 FCHL subjects were diagnosed with previous CVD. All these different cardiovascular manifestations have been associated with a greater IMT in several studies.9,10,23 Indeed, in our study population, FCHL subjects with CVD tended to have an increased IMT compared with FCHL subjects without clinical signs of CVD and healthy control subjects (P=0.06, Table 2). It is possible that because of the small number of FCHL subjects with CVD and the variation of IMT in these CVD-positive FCHL subjects, the observed differences did not reach the significance level. When FCHL subjects with a history of CVD were excluded from the analyses, a significantly increased IMT in CVD-free FCHL subjects compared with healthy controls was still observed, with a difference of 57 µm (age- and sex-corrected P<0.01).
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The 11 FCHL subjects with previously diagnosed CVD were now excluded from further analyses. Subsequently, we studied whether FCHL-specific factors were related to IMT in each group studied separately. For the FCHL subjects separately, age- and sex-adjusted univariate Pearson correlations between IMT, lipid and apolipoproteins, blood pressure values, and surrogate markers of insulin resistance (all treated as continuous variables) are depicted in Table 3. The primary data of some correlations in the FCHL subjects and control subjects are depicted simultaneously in the Figure. Significantly positive correlations between TC, non-HDL cholesterol, and apoB were observed. Positive correlations between IMT and LDL-C, log insulin, HOMA, nonesterified fatty acids, BMI, and waist measurement were observed, although they did not reach the significance level of P<0.05. However, in the FCHL group, no correlation existed between IMT and blood pressure values and glucose concentrations. When the control group was analyzed separately, age- and sex-adjusted univariate Pearson correlations between IMT and BMI, SBP, and DBP were observed: r=0.23 and P=0.11 (not significant), r=-0.28 and P=0.047, and r=-0.28 and P=0.054 (not significant), respectively.
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Subsequently, multiple backward linear regression analysis was used to evaluate whether 1 of the correlated metabolic factors (P<0.2) in the FCHL subjects was the most dominant in predicting an increased IMT (Table 4). Age and sex were also included as potentially contributing variables to an increased IMT. TC or non-HDL cholesterol, insulin or HOMA, respectively, were used in the regression analyses because of the close interaction between both of these variables. However, this did not alter the final results. These analyses revealed that apoB, besides age and sex, and in combination with BMI, which showed borderline significance, was related to an increased IMT (Table 4). This model explained almost 50% of the variance in IMT in our FCHL subjects.
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Discussion |
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The present study is the first to show that FCHL subjects had an increased IMT compared with healthy control subjects. FCHL subjects with a known history of CVD tended to have an even more increased IMT, as expected from reported associations between higher IMT with higher risk of clinical manifestations of CVD.9,10,23 The increased IMT observed in FCHL is in line with their known high risk of fatal and nonfatal CVD,4,5 which adds to the potential clinical value of the present observation. The annual progression rate of IMT has been estimated to be
6 to 10 µm.24–26 Therefore, the observed increase of 57 µm in IMT in FCHL subjects without previous CVD (mean age 48.5 years) corresponds to 5 to 9 years of physiological IMT increase, in excess of the average IMT found in age- and sex-matched control subjects. However, because the present study was a cross-sectional study, data on the true annual progression rate of IMT in FCHL subjects are presently not available.
In the FCHL study group, 24 (41.3%) of 58 subjects were being treated with a statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Thus, the observed IMT in FCHL is probably even underestimated, because antihyperlipidemic treatment with statins has been shown to slow the progression of IMT or even to reverse IMT.24–27 The presently observed higher IMT is also in line with the occurrence of dyslipidemia 15 to 20 years earlier in FCHL subjects compared with the general population.28
In the present study, well-known metabolic risk factors of atherosclerosis development, including lipids and apolipoproteins, were univariately associated with an increase in IMT in our FCHL population. Multivariate regression analyses revealed that age, sex, and apoB were independently related to the IMT in FCHL subjects. The effects of age and sex on IMT have been described extensively6 and are expected to be operational in all western populations. The relationship between IMT and increased apoB concentrations is clinically more important, because all apoB-containing lipoproteins are potentially atherogenic. Moreover, in cross-sectional29,30 and prospective31,32 studies, apoB has been shown to be a good risk indicator of CVD compared with other lipid levels or smoking, diabetes mellitus, and hypertension. In addition, apoB lowering has been shown to result in regression of CAD.33
Furthermore, FCHL is characterized by an overproduction of apoB-containing lipoproteins, which results in increased VLDL13 and LDL concentrations34 and the presence of small dense LDL particles.35,36 Because each lipoprotein particle (VLDL, IDL, LDL, chylomicrons, and chylomicron remnants) contains 1 apoB molecule, an increased apoB concentration is an indicator of increased numbers of circulating lipoproteins. In addition, in FCHL, a relative impairment in lipoprotein catabolism14 and an increased residence time of VLDL particles, both contributing to higher lipoprotein remnant concentrations, have been documented. Increased flux of atherogenic lipoproteins through the arteries, with (in addition) increased residence time, is a plausible mechanism for increased exposure of the endothelium to atherogenic lipoproteins in FCHL subjects. The present data indicate that increased apoB concentrations, reflecting increased delivery of atherogenic lipoproteins to the endothelium and the vessel wall, are closely related to an increased IMT and, with time, may be associated with clinical cardiovascular sequelae.
In the present study, increased BMI tended toward an association with higher IMT, but statistical significance was not reached (P=0.054). Increased BMI is potentially proatherogenic in humans through several pathophysiological mechanisms, including associated hyperlipidemia, hypertension, and insulin resistance. Increased BMI has been associated with an increased risk of developing CVD, in which cosegregation with associated metabolic disorders further enhances cardiovascular risk.37 In FCHL, abdominal obesity has been associated with increased risk of nonfatal CAD5 and hypertension.16 Furthermore, increased free fatty acid flux from visceral fat directly to the liver can contribute to a hypersecretion of apoB-containing TG-rich VLDL from the liver.38 Moreover, BMI reduction has been associated with reduced secretion of apoB-containing particles from the liver.38,39 Therefore, BMI reduction is a potentially important therapeutic goal in FCHL for the reduction of apoB secretion and lowering of blood pressure.16 In addition, because of its potential relationship with IMT in the FCHL subjects studied, BMI reduction may have an additional beneficial effect on IMT.
In conclusion, common carotid artery IMT is increased in FCHL subjects with a mean age of 48.5 years. In the present study, this increase in IMT corresponded to an acceleration of asymptomatic atherosclerosis by 5 to 9 years. The present novel findings show the important relationship of an increased number of lipoprotein particles and an increased IMT in FCHL. The reduction of abdominal obesity should be tested as a potential therapeutic intervention in FCHL for reducing the secretion of apoB-containing lipoproteins and potentially influencing IMT. Moreover, early detection of FCHL subjects, with subsequent dietary and/or drug treatment, is warranted because the development of asymptomatic atherosclerosis, which is associated with future cardiovascular events, is seriously enhanced in these subjects.
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Acknowledgments |
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The study was supported by a grant from the Academic Hospital Maastricht. We thank Margee Robertus-Teunissen and Vicky Vermeulen for expert technical assistance.
Received September 6, 2001; accepted November 12, 2001.
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References |
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 M De Michele, A Iannuzzi, A Salvato, P Pauciullo, M Gentile, G Iannuzzo, S Panico, A Pujia, G M Bond, and P Rubba Impaired endothelium-dependent vascular reactivity in patients with familial combined hyperlipidaemia Heart, January 1, 2007; 93(1): 78 - 81. [Abstract] [Full Text] [PDF]
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 A. D. Sniderman Apolipoprotein B Versus Non-High-Density Lipoprotein Cholesterol: And the Winner Is... Circulation, November 29, 2005; 112(22): 3366 - 3367. [Full Text] [PDF]
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T. Pischon, C. J. Girman, F. M. Sacks, N. Rifai, M. J. Stampfer, and E. B. Rimm Non-High-Density Lipoprotein Cholesterol and Apolipoprotein B in the Prediction of Coronary Heart Disease in Men Circulation, November 29, 2005; 112(22): 3375 - 3383. [Abstract] [Full Text] [PDF]
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N. Sattar, K. Williams, A. D. Sniderman, R. D'Agostino Jr, and S. M. Haffner Comparison of the Associations of Apolipoprotein B and Non-High-Density Lipoprotein Cholesterol With Other Cardiovascular Risk Factors in Patients With the Metabolic Syndrome in the Insulin Resistance Atherosclerosis Study Circulation, October 26, 2004; 110(17): 2687 - 2693. [Abstract] [Full Text] [PDF]
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 M. C. Carr and J. D. Brunzell Abdominal Obesity and Dyslipidemia in the Metabolic Syndrome: Importance of Type 2 Diabetes and Familial Combined Hyperlipidemia in Coronary Artery Disease Risk J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2601 - 2607. [Abstract] [Full Text] [PDF]
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C. Verseyden, S. Meijssen, H. van Dijk, H. Jansen, and M. C. Cabezas Effects of atorvastatin on fasting and postprandial complement component 3 response in familial combined hyperlipidemia J. Lipid Res., November 1, 2003; 44(11): 2100 - 2108. [Abstract] [Full Text] [PDF]
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C.J.M. Halkes, H. van Dijk, C. Verseyden, P.P.Th. de Jaegere, H.W.M Plokker, S. Meijssen, D.W. Erkelens, and M. C. Cabezas Gender Differences in Postprandial Ketone Bodies in Normolipidemic Subjects and in Untreated Patients With Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1875 - 1880. [Abstract] [Full Text] [PDF]
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M. M. J. van Greevenbroek, V. M. M-J. Vermeulen, and T. W. A. de Bruin Familial combined hyperlipidemia plasma stimulates protein secretion by HepG2 cells: identification of fibronectin in the differential secretion proteome J. Lipid Res., November 1, 2002; 43(11): 1846 - 1854. [Abstract] [Full Text] [PDF]
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P. M. H. Eurlings, C. J. H. van der Kallen, J. M. W. Geurts, P. Kouwenberg, W. D. Boeckx, and T. W. A. de Bruin Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia J. Lipid Res., June 1, 2002; 43(6): 930 - 935. [Abstract] [Full Text] [PDF]
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 H. Allayee, K. L. Krass, P. Pajukanta, R. M. Cantor, C. J.H. van der Kallen, R. Mar, J. I. Rotter, T. W.A. de Bruin, L. Peltonen, and A. J. Lusis Locus for Elevated Apolipoprotein B Levels on Chromosome 1p31 in Families With Familial Combined Hyperlipidemia Circ. Res., May 3, 2002; 90(8): 926 - 931. [Abstract] [Full Text] [PDF]
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H. Allayee, K. L. Krass, P. Pajukanta, R. M. Cantor, C. J.H. van der Kallen, R. Mar, J. I. Rotter, T. W.A. de Bruin, L. Peltonen, and A. J. Lusis Locus for Elevated Apolipoprotein B Levels on Chromosome 1p31 in Families With Familial Combined Hyperlipidemia Circ. Res., May 3, 2002; 90(8): 926 - 931. [Abstract] [Full Text] [PDF]
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