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(Circulation. 1998;97:34-40.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Echo-Lucency of Computerized Ultrasound Images of Carotid Atherosclerotic Plaques Are Associated With Increased Levels of Triglyceride-Rich Lipoproteins as Well as Increased Plaque Lipid Content

Marie-Louise M. Grønholdt, MD; Børge G. Nordestgaard, MD, DMSc; Britt M. Wiebe, MD; Jens E. Wilhjelm, MSEE, PhD; ; Henrik Sillesen, MD, DMSc

From the Department of Vascular Surgery, Rigshospitalet, (M.-L.M.G.), Department of Clinical Biochemistry, Herlev Hospital (B.G.N.), Laboratory of Neuropathology, Rigshospitalet (B.M.W.), and Department of Vascular Surgery, Gentofte Hospital (H.S.), University Hospital of Copenhagen, Denmark, and the Department of Information Technology, Technical University of Denmark (J.E.W.).

Correspondence to Dr Marie-Louise Moes Grønholdt, Department of Vascular Surgery, RK 3112, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: mlg{at}rh.dk

	Abstract

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Background—Echo-lucency of carotid atherosclerotic plaques on computerized ultrasound B-mode images has been associated with a high incidence of brain infarcts as evaluated on CT scans. We tested the hypotheses that triglyceride-rich lipoproteins in the fasting and postprandial state predict carotid plaque echo-lucency and that echo-lucency predicts a high plaque lipid content.

Methods and Results—The study included 137 patients with neurological symptoms and 50% stenosis of the relevant carotid artery. High-resolution B-mode ultrasound images of carotid plaques were computer processed to yield a measure of echogenicity (gray-scale level). Lipoproteins were measured before and hourly for 4 hours after a standardized fatty meal. A subgroup of 58 patients underwent endarterectomy. On linear regression analysis, echo-lucency (low gray-scale level) was associated with elevated levels of fasting and postprandial plasma triglycerides (P=.0002 and P=.002), IDL cholesterol (P=.0009 and P=.006), and VLDL/chylomicron remnant cholesterol (P=.0003 and P=.0004) and triglycerides (P=.0003 and P=.003), the area under the plasma triglyceride curve 0 to 4 hours after a fatty meal (P=.001), and body mass index (P=.0001). On ANCOVA, body mass index, fasting IDL cholesterol, and fasting plasma triglycerides were independent predictors of echo-lucency. Echo-lucency was associated with increased relative plaque lipid content (P=.02).

Conclusions—Increased plasma levels of triglyceride-rich lipoproteins predict echo-lucency of carotid plaques, which is associated with increased plaque lipid content. Because echo-lucency has been associated with a high incidence of brain infarcts on CT scans, triglyceride-rich lipoproteins may predict a plaque type particularly vulnerable to rupture.

Key Words: arteriosclerosis • carotid arteries • ultrasonics • lipoproteins • pathology

	Introduction

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Low density lipoprotein cholesterol is causally related to the development of atherosclerosis,^{1 2} and a reduction in LDL levels leads to reduced progression of atherosclerosis,^{3 4} reduced incidence of myocardial infarction^{5 6 7} and stroke,^{5 7} and even reduced total mortality.^{5 6} The role of triglyceride-rich lipoproteins is much less clear. Nevertheless, elevated plasma triglyceride levels have repeatedly been associated with an increased incidence of myocardial infarction,⁸ and three intervention trials have provided some evidence that a reduction in triglyceride-rich lipoproteins is associated with a reduction in the progression of coronary atherosclerosis⁹ and the incidence of coronary events.^{9 10 11}

In a recent study, we demonstrated that elevated plasma levels of triglyceride-rich lipoproteins in the fasting or postprandial state were associated with echo-lucent carotid artery plaques as evaluated subjectively by B-mode ultrasonography.¹² Weak reflection of ultrasound from carotid atherosclerotic plaques, ie, echo-lucency, is also associated with a higher histological content of lipids,¹³ as well as with increased risk of developing neurological symptoms.^{14 15 16 17} It is therefore conceivable that elevated plasma levels of triglyceride-rich lipoproteins may be associated with atherosclerotic plaques, with lipid-rich cores particularly prone to rupture and causing neurological symptoms, and that such plaques can be diagnosed noninvasively and subjectively as echo-lucent plaques on B-mode ultrasonography.

Recently, computerized assessment of plaque echogenicity (measured as gray-scale level) has been introduced as a more quantitative and objective method of ultrasonographic plaque characterization.^{18 19 20} With this improved method, a high fibrous tissue content was associated with a high gray-scale value (echo-rich plaque), whereas a high lipid and hemorrhage content was associated with a low gray scale value (echo-lucent plaque).²⁰ In addition, plaque echo-lucency was associated with a higher incidence of brain infarcts as assessed with CT scans.^{18 19}

In this study, we tested the hypotheses that (1) elevated plasma levels of triglyceride-rich lipoproteins in the fasting or postprandial state predict echo-lucency of carotid atherosclerotic plaques on computerized ultrasound B-mode imaging and (2) echo-lucency predicts increased relative plaque lipid content.

	Methods

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Subjects
Consecutive symptomatic patients (96 men and 41 women; median age, 64 years) were enrolled. Symptoms were stroke (n=77 or 56%), transient ischemic attack (n=45 or 33%), or amaurosis fugax (n=15 or 11%). Criteria for entry into the study were a degree of carotid stenosis of 50% on the symptomatic side, no use of lipid-lowering medications, and a willingness to perform the fat tolerance test. Fifty-eight of these patients underwent carotid endarterectomy. Patients performed the fat tolerance test either 3 months after inclusion or 3 months after carotid endarterectomy. Collection of basic characteristics has been described previously.¹² The study was approved by the medical ethics committee for Copenhagen and Frederiksberg counties (No. KF 01- 062/94), and all patients gave informed consent.

Ultrasound Examination
All patients had their carotid artery on the symptomatic site ultrasound scanned with an Interspec RX 400 with a 5- to 10-MHz linear array transducer. Degree of stenosis was determined by routine Doppler criteria.¹² Furthermore, high-resolution B-mode and color Doppler images of the plaque from the anterior, lateral, and cross-sectional scan plane were evaluated on-line by use of the criteria of the European Multicenter Study on Plaque Morphology: echogenicity was evaluated as either echo-rich, intermediate, or echo-lucent.^{12 13} In addition, representative images were captured from a videotape of the ultrasound examination and digitized with a Targa 2000-E framegrabber (20 MB PAL, Truevision Inc). The B-mode and corresponding color Doppler images were processed with the software program Image-Pro Plus, version 1.2.01 for Windows (Media Cybernetics); the carotid artery plaque was outlined and the gray-scale value of each pixel in the region was used to generate a median gray scale value (see the Figure 1); in case of acoustic shadowing from a plaque, the outline did not include this shadow region. In the histogram in the Figure, the number of pixels with a given gray-scale value in the outlined region is plotted against the gray-scale level (0 to 255; 0=black and 255=white).

View larger version (49K): [in this window] [in a new window]   Figure 1. Ultrasound B-mode image of a carotid artery plaque. Outline (excluding the acoustic shadowing) shows the plaque area where gray-scale levels of all pixels are used to construct the histogram showing distribution of gray-scale level among pixels. Median of the gray-scale level is used for further analysis.

At the beginning of each ultrasound examination, the gain setting was set so that blood visually appeared black. To validate this standardization approach, an area of blood was also outlined for each patient on the B-mode ultrasound image, showing an average median gray-scale value of 38.3±2.1 (mean±SD). The difference in gray-scale level between the region of the atherosclerotic plaque and blood was calculated for each patient, and this adjusted gray-scale value for the atherosclerotic plaque was used to recalculate all the statistics presented in "Results." Whether unadjusted or adjusted gray-scale levels were used, the main results and conclusions were the same. We therefore chose to show results based on unadjusted gray-scale levels throughout this article. Ultrasound examinations including generation of outlines were all performed by a single experienced ultrasonographer (M.-L.M.G.) who was unaware of the fat tolerance test values and histological examinations.

Fat Tolerance Test
After a 12-hour overnight fast, all patients were given a fatty meal consisting of 1 g dairy cream fat per 1 kg body weight. Plasma lipids and lipoproteins were measured before and at hourly intervals for 4 hours after the fatty meal, as described elsewhere.¹² The magnitude of postprandial triglyceridemia and cholesterolemia was calculated as the area under the plasma cholesterol (AUC_C, AUC_{C-C 0h}) and triglyceride (AUC_TG, AUC_{TG-TG 0h}) curves 0 to 4 hours after a fatty meal.¹²

Histological Examination
In 58 patients, the carotid artery plaques were removed in toto during endarterectomy. After the external carotid artery was discarded, the remaining plaque was cut transversely into 3-mm-thick blocks (4 to 14 per patient). Consecutive sections from each block were stained with hematoxylin and eosin, Van Gieson's, and Verhoeff's stain, respectively. Plaque constituents (lipid, hemorrhage, calcification, thrombus, and fibrous tissue) in all sections were measured morphometrically by a single experienced pathologist (B.M.W.) using a Leitz Texture Analyzing System (TAS).

The total volume of each constituent in the removed plaque was calculated as the sum of the area of the individual constituent in all blocks multiplied by the mean distance in millimeters between each section. The relative volume of each constituent was calculated as the total volume of that constituent divided by the total volume of all four constituents. The pathologist was unaware of values from the ultrasound examination and fat tolerance test.

Reproducibility
The same ultrasonographer (M.-L.M.G.) reexamined 58 consecutively chosen images; new outlines of carotid artery plaques were created to obtain new gray-scale values, with the ultrasonographer unaware of the first outlines of the plaques performed 3 to 6 months earlier. Likewise, the pathologist (B.M.W.) reexamined 10 randomly chosen plaques morphometrically, without knowledge of the values from the first examination. The reproducibility of plasma lipid and lipoprotein measurement during a fat tolerance test seems to be as good as those for fasting levels.²¹

Statistical Analysis
Student's t test, ANOVA, ² test, univariate linear regression, and ANCOVA (forward stepwise method) were performed with the Statistica program.²² Predictors significant (P.05) on univariate linear regression analysis or on the t test entered the ANCOVA. To approach normal distribution, medians of gray-scale values; plaque volumes; lipoprotein(a); triglycerides in plasma, IDL, and VLDL; cholesterol in IDL and VLDL; and AUC_TG and AUC_{TG-TG 0h} were all transformed logarithmically before statistical tests. Reproducibility was tested with the method of Bland and Altman,²³ in which the difference between two repeated measurements was plotted against the mean of the same two measurements to calculate a mean bias with 95% confidence interval. A coefficient of variation based on duplicate measurements was also calculated. A probability value of P.05 on two-sided tests was considered statistically significant.

	Results

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There were no major differences in the characteristics of the 137 symptomatic patients with 50% stenosis of the relevant carotid artery compared with the subgroup of 58 patients who had their carotid plaque removed by endarterectomy (Tables 1 and 2). The average degree of stenosis in the total group of patients and in the endarerectomy subgroup was 81%±2% and 71%±2% (mean±SEM), respectively.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients With Carotid Artery Plaques

View this table: [in this window] [in a new window]   Table 2. Age, BMI, and Biochemical Characteristics of Patients With Carotid Artery Plaques

Qualitative Plaque Characteristics
Gray-Scale Median
The gray-scale level of carotid atherosclerotic plaques was negatively associated with fasting and postprandial levels of plasma triglycerides, IDL cholesterol, VLDL/chylomicron remnant cholesterol and triglycerides, the area under the plasma triglyceride curve 0 to 4 hours after a fatty meal, and body mass index (BMI) (Table 3). BMI was positively associated with most characteristics of triglyceride-rich lipoproteins and negatively associated with HDL cholesterol (data not shown).

View this table: [in this window] [in a new window]   Table 3. Univariate Linear Regression Analysis of Age, BMI, and Biochemical Characteristics as Predictors of Ultrasonic Gray-Scale Median, Total Plaque Volume, Total Plaque Lipid, and Total Plaque Fibrous Tissue of Carotid Artery Plaques

When ANCOVA was performed, BMI, fasting IDL cholesterol, and fasting plasma triglycerides were independent predictors of gray-scale median values (Table 4). If this analysis was based on gray-scale level adjusted for gray-scale level of blood (see "Methods"), the independent predictors of plaque gray-scale values were fasting plasma triglycerides (P=.0004) and fasting IDL cholesterol (P=.02).

View this table: [in this window] [in a new window]   Table 4. Ranking by ANCOVA of Independent Predictors of Gray-Scale Median, Total Plaque Volume, and Total Plaque Lipid and Fibrous Tissue of Carotid Artery Plaques

Relative plaque lipid content (39.8±1.7%; mean±SEM) was negatively associated, and relative plaque fibrous tissue content (58.5±1.7%) was positively associated with gray-scale median level (Table 5). Relative plaque content of calcification (1.2±0.2%) or hemorrhage (0.5±0.1%) was not associated with gray-scale median level (data not shown). Subjective evaluation of plaque echogenicity (echo-lucent versus intermediate versus echo-rich) was associated with computer-assisted measurement of gray scale median values (Table 5); echo-lucency of the plaque was associated with low gray-scale medians.

View this table: [in this window] [in a new window]   Table 5. Comparison of the Objective Computer-Assisted Measurement of Gray-Scale Median With Relative Lipid and Fibrous Tissue in Plaques Measured Histomorphometrically as Well as With the Subjective Evaluation of Plaque Echogenicity

Histology
On univariate linear regression analysis, total plaque volume, total plaque lipid, and total plaque fibrous tissue were directly related to age, BMI, and fasting and postprandial LDL cholesterol, whereas they were inversely related to fasting and postprandial levels of HDL cholesterol (Table 3). Of the characteristics shown in Table 1, sex alone predicted total plaque volume (Student's t test, P=.00005) and total plaque lipid (P=.000003). Sex and diabetes mellitus both predicted total plaque fibrous tissue (P=.000001 and P=.01). On ANCOVA, sex, BMI and fibrinogen were independent predictors of total plaque volume; sex and fasting LDL cholesterol were independent predictors of total plaque lipid; and sex, BMI, and fasting LDL cholesterol were independent predictors of total plaque fibrous tissue (Table 4).

Reproducibility
When 58 computerized digital images had carotid plaque outlines redrawn to recalculate gray-scale median levels, the mean bias between the two independent determinations of gray-scale median values was -0.4 (95% confidence interval [CI], -1.5 to 0.1). Likewise, the mean bias for a repeated measurement (n=10) of relative plaque lipid and fibrous tissue content was 0.6% (95% CI, -1.5% to 2.6%) and 1.1% (95% CI, -0.8% to +3.1%), respectively. The coefficients of variation for these three measurements based on the repeated analysis were 5.5%, 3.5%, and 2.2%, respectively.

	Discussion

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Echo-lucency on subjective evaluation and a low gray-scale value (echo-lucency) on objective computer-assisted evaluation of carotid atherosclerotic plaques have previously been associated with an increased incidence of neurological symptoms^{14 15 16 17} and an increased incidence of nonsymptomatic brain infarction on CT scans,^{18 19} respectively.

One important new observation in the present study is that elevated plasma levels of triglyceride-rich lipoproteins in the fasting or postprandial state predict echo-lucency (measured as a low gray-scale level) of computerized ultrasound images of carotid atherosclerotic plaques. This is in accordance with our previous findings using subjective evaluation of plaque echogenicity.¹² Subjective evaluation of plaque echogenicity was found in the present study to correlate well with the objective computer-assisted evaluation, which had an intraobserver coefficient of variation of 5.5%. Other previous studies found that elevated plasma levels of triglyceride-rich lipoproteins in the fasting or postprandial state (IDL, VLDL, chylomicron remnants, and postprandial triglycerides) were predictors of the presence, severity, progression, or familial risk of atherosclerosis^{24 25 26 27 28 29 30 31 32 33 34 35} ; however, none of these studies examined qualitative plaque characteristics as in the present study.

Another important observation in the present study is that echo-lucency of carotid atherosclerotic plaques was a predictor of increased relative plaque lipid content within a subgroup of patients undergoing carotid endarterectomy. This is in accordance with findings in previous studies using either subjective¹³ or objective²⁰ computer-assisted evaluation of plaque echogenicity. A high gray-scale value was associated with a high relative plaque fibrous tissue content in the present study and in a previous study.²⁰

The present and former^{12 13 14 15 16 17 18 19} studies together support the hypothesis that elevated plasma levels of triglyceride-rich lipoproteins in the fasting or postprandial state promote development of atherosclerotic plaques with lipid-rich cores and that such plaques are particularly vulnerable to rupture, thereby causing embolism and subsequent neurological symptoms like stroke, transient ischemic attack, or amaurosis fugax. Like LDL, triglyceride-rich lipoproteins can transfer from plasma into the arterial intima,^{36 37} where such particles appear to be retained selectively.^{37 38} In contrast to LDL, however, triglyceride-rich lipoproteins without prior modification can then be taken up directly by macrophages to produce lipid-rich foam cells,³⁹ a key cell type of the atherosclerotic plaque.⁴⁰

In our former study,¹² indexes of elevated VLDL/chylomicron remnant levels were primarily associated with echo-lucency of carotid atherosclerotic plaques, whereas in this study, elevated IDL cholesterol levels also were associated with echo-lucency, ie, with a low gray-scale level. Both VLDL/chylomicron remnant and IDL particles represent smaller triglyceride-rich lipoproteins in plasma, and the cholesterol contents of these two types of particles are positively associated (data not shown). A likely explanation for the small discrepancy between the two studies is the greater statistical power of the present study, the inclusion of more patients (137 versus 85), and the use of a more objective measurement of plaque echogenicity. In both studies, high BMI values were associated with echo-lucency or low gray-scale values, and in this study, BMI was the strongest independent predictor of low gray-scale levels. This association could potentially also be explained by triglyceride-rich lipoproteins because BMI is positively associated with all indexes of triglyceride-rich lipoproteins; however, the data cannot exclude that BMI, either by itself or through yet another risk factor like low HDL cholesterol levels associated with BMI, has an effect on plaque echogenicity independent of triglyceride-rich lipoproteins.

Interestingly, we found that triglyceride-rich lipoproteins predicted the qualitative plaque characteristic of gray-scale level on ultrasound B-mode images, whereas the most significant lipid predictors of quantitative plaque characteristics like total plaque volume, total plaque lipid, and total plaque fibrous tissue were LDL cholesterol directly and HDL cholesterol inversely. These associations between LDL and HDL cholesterol and the extent of atherosclerosis are well recognized.^{1 2 41} The difference in predictors between qualitative and quantitative plaque characteristics supports the notion that triglyceride-rich lipoproteins in particular are involved in the development of plaques with lipid-rich cores, whereas LDL and HDL levels are important determinants of the extent and severity of atherosclerosis. A reduction in LDL cholesterol levels,^{5 6 7} increases in HDL cholesterol levels,¹⁰ and a reduction in levels of triglyceride-rich lipoproteins in plasma^{9 10 11} all seem to be associated to some extent with a reduced incidence of cardiovascular events.

In conclusion, elevated plasma levels of triglyceride-rich lipoproteins in the fasting or postprandial state appear to predict echo-lucency of carotid atherosclerotic plaques, which is associated with increased plaque lipid content and an increased incidence of brain infarction on CT images. Triglyceride-rich lipoproteins may therefore predict a plaque type particularly vulnerable to rupture and thus leading to embolism and neurological symptoms. Computer-assisted analysis of high-resolution B-mode ultrasound images may improve the diagnoses of patients with particularly vulnerable plaques and may in the future play an important role in the selection of patients for carotid endarterectomy. Furthermore, the present data might ultimately lead to strategies for identifying patients who might benefit from specific lipid-lowering therapies, ie, those with echo-lucent plaques, increasing the cost-effectiveness of such therapy.

	Acknowledgments

 
This study was supported by the Danish Medical and Technical Research Council. We appreciate the technical assistance of Hanne Damm, Anne Merete Bengtsen, Ann Meisler, and Birgitte Søe Hansen.

Received April 29, 1997; revision received July 17, 1997; accepted July 20, 1997.

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