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(Stroke. 1996;27:2166-2172.)
© 1996 American Heart Association, Inc.

Articles

Echolucent Carotid Artery Plaques Are Associated With Elevated Levels of Fasting and Postprandial Triglyceride-Rich Lipoproteins

Marie-Louise Moes Grønholdt, MD; Børge G. Nordestgaard, MD, DMSc; Tina G. Nielsen, MD Henrik Sillesen, MD, DMSc

the Department of Vascular Surgery, Rigshospitalet, and the Department of Clinical Biochemistry, Herlev Hospital (B.G.N.), University of Copenhagen (Denmark).

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Echolucent carotid atherosclerotic plaques are associated with an increased risk of neurological symptoms. Elevated plasma triglycerides is a risk factor for cerebral and coronary infarction. This study examined these individual pathogenetic risk factors to determine whether they were related.

Methods We included 85 symptomatic patients with at least 40% carotid artery stenosis. Plaque morphology of the relevant artery was evaluated by high-resolution B-mode ultrasonography as echolucent, echo-rich, or intermediate. Fasting and postprandial lipids and lipoproteins were measured before and at hourly intervals for 4 hours after a fatty meal (1 g cream fat per kilogram body weight).

Results When we compared patients with echolucent plaques to patients with echo-rich or intermediate plaques, the former had higher fasting and postprandial plasma triglycerides (P.006), higher chylomicron remnants/VLDL cholesterol (P=.02) and triglycerides (P.004), a larger area under the plasma triglyceride curve 0 to 4 hours after a fatty meal, with (AUC_{TG-TG 0h}) or without (AUC_TG) subtraction of fasting levels (P=.007 and P=.003), a larger body mass index (P=.03), and were younger (P=.01). Multiple logistic regression analysis found that when age and body mass index were taken into account, fasting plasma and VLDL triglycerides, postprandial chylomicron remnants/VLDL triglycerides, AUC_{TG-TG 0h} and AUC_TG with odds ratios of 4.1, 3.8, 3.0, 2.7, and 4.3, respectively, were independent predictors of an echolucent plaque.

Conclusions Echolucent carotid artery plaques are associated with elevated levels of triglyceride-rich lipoproteins in the fasting or postprandial state.

Key Words: arteriosclerosis • carotid artery diseases • lipoproteins • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Elevated plasma cholesterol, ie, LDL cholesterol, is causally related to the development of atherosclerosis.^{1 2} Double-blind intervention trials have demonstrated that reduction in plasma and LDL cholesterol levels leads to reduced progression or even regression of atherosclerotic plaques in coronary,^{3 4} femoral,⁵ and carotid arteries^{6 7 8 9} but also reduction in the incidence of myocardial infarction,^{10 11} cerebrovascular events,¹⁰ and even death.^{10 11} Reduction in the incidence of myocardial infarction after lowering of triglyceride-rich lipoproteins in plasma has only been demonstrated in a subgroup analysis of the Helsinki Heart Study.¹²

The mechanism behind the reduction in cerebrovascular events and myocardial infarction following reduction in LDL or perhaps triglyceride-rich lipoproteins was originally thought to build on the reduction in plaque size, opening up the vessel to a larger blood flow.¹³ More recently, however, it has been suggested that plasma cholesterol reduction causes a reduction in the lipid content of plaques with a lipid-rich core and a thin fibrous cap, thereby reducing the likelihood that these otherwise vulnerable plaques will rupture, causing either an embolism or thrombosis leading to infarction.^{14 15} A better understanding of this process, particularly of the development of atherosclerotic plaques with lipid-rich cores compared with other plaque types, may help us to prevent clinical cardiovascular and cerebrovascular events rather than focusing only on the volumetric size of atherosclerotic plaques.

With the use of high-resolution ultrasound B-mode imaging, carotid plaques that only poorly reflect the emitted ultrasound signals (echolucent) have been shown to have a higher histological content of lipid and hemorrhage than plaques that strongly reflect ultrasound.¹⁶ The latter echo-rich plaques had a higher content of fibrous tissue than the former.¹⁶ Recent studies also indicate that echolucent compared with echo-rich carotid lesions are associated with a higher risk of development of neurological symptoms and brain infarctions.^{17 18 19}

We therefore studied 85 symptomatic patients with clinically important carotid atherosclerosis on the symptomatic side in a study aimed at finding determinants of an echolucent atherosclerotic plaque on B-mode ultrasonography.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
From January to July 1995, eighty-five patients with carotid artery disease (60 men and 25 women; median age, 67 years; range, 37 to 79 years) were examined. These patients were recruited from consecutive referrals for carotid ultrasound examination at the Department of Vascular Surgery, Rigshospitalet, Copenhagen, and all had experienced neurological symptoms from the same side as the carotid artery examined: stroke (n=60 [71%]), transient ischemic attack (n=17 [20%]), or amaurosis fugax (n=8 [9%]). Criteria for entry into the study were as follows: (1) a degree of carotid stenoses over 40% on the symptomatic side, (2) no use of lipid-lowering medications, and (3) willingness to perform the fat tolerance test. Eleven patients had the fat tolerance test 3 months after endarterectomy of their symptomatic carotid artery; the remaining 74 patients had contraindications to surgery: age over 70 years (n=25), disabling stroke (n=5), severe hypertension (n=16), or severe cardiac disease (n=28). In these 74 cases, the fat tolerance test was performed on the same day as the ultrasound examination.

Age, sex, height, and weight were registered. Subjects with cardiac disease were grouped as having angina pectoris, cardiac failure, or myocardial infarction, and cardiovascular risk factors were noted: family history of myocardial infarction or stroke (first-degree relatives who before the age of 60 years experienced a myocardial infarction or stroke), hypertension (current or previous use of antihypertensive drugs and/or blood pressure 160/95 mm Hg), diabetes mellitus (taking oral hypoglycemic agents or insulin or being treated with an antidiabetic diet), and smoking habits (nonsmoker, past smoker if subjects stopped smoking less than 10 years ago, or current smoker). BMI was calculated as weight divided by height². The study protocol was approved by the medical ethics committee for Copenhagen and Frederiksberg counties (KF 01-062/94). Informed consent was obtained from all participants of the study.

Ultrasound Investigation
We evaluated the carotid arteries with high-resolution B-mode ultrasonography and color-Doppler duplex examination using an Interspec RX 400 with a 5- to 10-MHz linear array transducer. Plaque echogenicity, structure, and surface were characterized according to the criteria of the European Carotid Plaque Study Group¹⁶ : echogenicity was classified as strong (echo-rich), intermediate, or weak (echolucent); plaque structure was described as homogeneous or heterogeneous; and the surface was described as either regular, irregular, or not possible to evaluate. Degree of stenosis was determined by generally accepted Doppler criteria²⁰ and separated into 0% to 15%, 16% to 49%, 50% to 79%, and 80% to 99% stenosis and occlusion.

All ultrasound examinations were performed by a single investigator (M.-L.M.G.), and grading of echogenicity, structure, surface characteristics, and percent stenosis was done during the examination.

Fat Tolerance Test
After a 12-hour overnight fast, all patients were given a fatty meal: 38 g dairy cream fat per 100 mL in a dose of 1 g fat per kilogram body weight. This amount of fat corresponds to one half to two thirds of the daily ingestion of fat for individuals in affluent countries.²¹ Plasma cholesterol and triglyceride concentrations were measured before and hourly up to 4 hours after the fatty meal; because most patients were either elderly or suffering from diabetes mellitus, they were only asked to undergo a 4-hour fat tolerance test rather than 8 or more hours. No food or beverages other than water were allowed during the study period. The fat tolerance test was performed on the same day as the evaluation of the carotid artery plaque from the B-mode image, and the sonographer was therefore blinded to the lipid/lipoprotein results.

Biochemical Analysis
Blood samples (10 mL at 0 and 4 hours; 3 mL at 1, 2, and 3 hours) were collected in tubes containing Na₂EDTA (1.2 mg/mL), and plasma was isolated at 20°C. Lipoproteins were separated with ultracentrifugation with the use of a Beckman 50.3 Ti, a Beckman 50.4 Ti, or a Kontron TFT 45.6 rotor at 4°C for at least 2.8x10⁶gxhours. Solvent densities of 1.006, 1.019, and 1.063 g/mL, respectively, were used to separate VLDL (d<1.006 g/mL), IDL (1.006 g/mL<d<1.019 g/mL), LDL (1.019 g/mL<d<1.063 g/mL), and HDL (d>1.063 g/mL); 4 hours after a fatty meal the d<1.006 g/mL fraction also includes CR and perhaps some chylomicrons and is therefore designated CR/VLDL. Cholesterol and triglycerides in plasma and lipoprotein fractions were determined enzymatically (CHOD PAP and GPO-PAP, Boehringer Mannheim). The average recoveries of cholesterol and triglycerides during ultracentrifugation were 96.8±0.5% and 98.3±0.8%, respectively (mean±SEM, n=255).

Lp(a) was measured turbidimetrically with rabbit anti-human Lp(a) polyclonal antibodies (DAKO A/S) and human serum Lp(a) calibrator (DAKO A/S). Fibrinogen was measured with standard hospital procedures (IL Test PT-Fibrinogen²² ).

Magnitude of postprandial triglyceridemia and cholesterolemia was calculated as the area under the plasma cholesterol (AUC_C) and triglyceride (AUC_TG) curves 0 to 4 hours after the fatty meal. The increase in plasma lipids after the fatty meal, ie, the area between the plasma curves and the respective concentrations at zero hour (fasting plasma), was also calculated (AUC_{TG-TG 0h} and AUC _{C-C 0h}).

Statistical Analysis
All statistical tests were performed with the Statistica program.²³ Differences in continuous and categorical variables between individuals with different ultrasound images of the carotid artery were evaluated with Kruskal-Wallis ANOVA and the ² test, respectively. In case of a significant ANOVA, post hoc analysis was performed with the Mann-Whitney U test.

A multiple logistic regression analysis with forced entry (Table 4) was performed to describe the relationship between the dependent variable (echolucent versus intermediate and echo-rich combined) and the lipids and lipoproteins found to be significant predictors on univariate analysis when age and BMI, fasting HDL cholesterol, and diabetes mellitus were considered. Intermediate and echo-rich categories were combined because individuals with these two types of ultrasound images were similar with regard to significant lipid values (Fig 1, Table 2). Since HDL cholesterol and diabetes mellitus are known to be related to plasma triglycerides, models were also built to include these parameters. The contribution of lipids/lipoproteins in predicting echogenicity in these models is expressed as an odds ratio (e^ß) with 95% confidence intervals (e^ß±1.96xSE). Significant contributions to the model of BMI, age, fasting HDL cholesterol, diabetes mellitus, and lipid/lipoproteins were tested by the likelihood-ratio test.

View this table: [in this window] [in a new window]   Table 4. Odds Ratios for Various Characteristics by Multiple Logistic Regression as Predictors of Echolucent Carotid Artery Plaques vs Intermediate and Echo-Rich Carotid Artery Plaques Combined

View larger version (78K): [in this window] [in a new window]   Figure 1. Ultrasound B-mode images of an echo-rich carotid artery plaque with acoustic shadowing beneath the plaque (top) and an echolucent carotid artery plaque (bottom). Arrows indicate luminal surface of the plaques. Distance between dots on right-hand scale is 2 mm. ICA indicates internal carotid artery; CCA, common carotid artery.

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

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Echogenicity of Carotid Artery Plaques
Examples of ultrasound B-mode images of an echolucent and echo-rich carotid artery plaque are shown in Fig 1. Patients with echolucent plaques were younger and had a larger BMI than patients with either echo-rich or intermediate plaques (Table 1). In the fasting state, plasma triglycerides and VLDL cholesterol and triglycerides were all increased in patients with echolucent plaques compared with other patients (Table 2). Likewise, at 1, 2, 3, and 4 hours after a fatty meal, plasma triglycerides were highest in the patients with echolucent plaques (Fig 2, Table 2), as were CR/VLDL cholesterol and triglycerides (Table 2). The AUC_TG from 0 to 4 hours after a fatty meal was also larger in patients with echolucent plaques than in patients with intermediate and echo-rich plaques, irrespective of whether total plasma triglyceride levels or the increase over fasting levels was examined (Fig 2, Table 2). When patients with diabetes mellitus were excluded, the same significant lipid/lipoprotein parameters, except fasting VLDL cholesterol (P=.07), were still significantly related to echogenicity of the plaque.

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

View larger version (22K): [in this window] [in a new window]   Figure 2. Plasma triglycerides as a function of time after a fatty meal in patients with plaques of different echogenicity (bottom). Top panel shows plasma triglyceride values after subtraction of fasting values. Values are mean±SEM, expressed in millimoles per liter. *P<.05, **P<.005 when mean values at the same time point of the three types of echogenicity are compared with Kruskal-Wallis ANOVA.

Table 3 shows correlation among characteristics predicting echogenicity on univariate analysis. Plasma triglycerides and CR/VLDL cholesterol and triglycerides, fasting or postprandial, and the AUC_TG, with and without fasting levels subtracted, were all highly positively correlated. BMI was correlated positively with the aforementioned lipid parameters but to a lesser extent than the intercorrelation among lipid parameters. Age was weakly negatively correlated with some lipid values but not with others (Table 3).

View this table: [in this window] [in a new window]   Table 3. Correlation Coefficients Among Characteristics Predicting Echogenicity of Carotid Artery Plaques on Univariate Analysis

To examine the independent effect of lipid parameters on echogenicity when age and BMI were considered, multiple logistic regression analysis was performed (Table 4). Then, fasting plasma and VLDL triglycerides, postprandial CR/VLDL triglycerides, and the AUC_TG, with and without subtraction of fasting levels, were still predictors of echolucent rather than combined echo-rich and intermediate carotid artery plaques. BMI did not have an independent effect in the multiple logistic regression model, whereas age still contributed significantly in explaining echogenicity. When fasting HDL cholesterol was added to the models shown in Table 4 instead of BMI and age, fasting VLDL triglycerides and postprandial CR/VLDL triglycerides as well as AUC_TG and AUC_{TG-TG 0h} were still predictors of echolucent carotid artery plaques. When diabetes mellitus instead of BMI and age was added to the models, all lipid values significant on univariate analysis (Table 2) were still significant predictors of echolucent plaques.

Structure and Surface of Carotid Artery Plaques
Homogeneous or heterogeneous carotid artery plaques could not be predicted by any of the characteristics shown in Tables 1 and 2. Plaques with a regular surface versus irregular surface were associated with a higher HDL triglyceride level (0.32 versus 0.17, P=.03) and a larger AUC_TG after subtraction of fasting levels (0.70 versus 0.37, P=.004).

Degree of Carotid Stenosis
Degree of stenosis was not associated with any of the characteristics shown in Tables 1 and 2.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Although the majority of previous pathological work investigating the pathogenesis of carotid artery disease focused on the extent and severity of atherosclerosis (luminal narrowing), recent work seems to indicate that plaque morphology may be important for the occurrence of clinical events.^{17 18 19 24 25}

Noninvasive ultrasound examination is well established for diagnosis and quantification of carotid artery disease.^{20 26} Not only can the severity of the stenosis be measured accurately, but the morphology of the lesion can also be evaluated with this technique. The relationship between plaque morphology as assessed by high-resolution B-mode imaging and prognosis has been addressed increasingly.^{17 18 19 24 25} Despite differences in ultrasound classifications of the plaque morphology, it is generally agreed that echolucent and heterogeneous plaques are associated with a higher risk of developing neurological symptoms than are echo-rich plaques. Moreover, the higher amount of soft tissue, ie, lipid and hemorrhage, associated with echolucent plaques has been shown to decline with time after symptoms.²⁶ This might imply that the older the plaque, the more echo-rich it may appear on ultrasound images and represent less risk of causing symptoms. It therefore seems likely that the morphology of the plaque—in addition to the degree of stenosis—is a predictor of the prognosis and may in the future play an important role in the selection of patients for carotid endarterectomy.

In the present study the most significant finding was that fasting as well as postprandial triglyceride concentrations in plasma and CR/VLDL were more elevated in patients with echolucent plaques than in patients with more echo-rich plaques. On the other hand, lipid values were not related to the degree of stenosis. Using a different measure of plaque severity, Ryu et al²⁷ showed an association between peak triglyceride response after a fatty meal and intima-media thickness measured with B-mode ultrasound. However, in that study no qualitative description of intimal morphology was given. Furthermore, several studies have shown that compared with control subjects, patients with coronary heart disease have an elevated plasma triglyceride response to a fatty meal.^{28 29 30 31 32 33 34 35} Taken together, the evidence suggests that triglyceride-rich lipoproteins in the postprandial state may be causally related to the development of atherosclerosis and its clinical manifestations; the present study extends this hypothesis to suggest that lipoproteins in the d<1.006 g/mL density range, ie, CR/VLDL, in particular are involved in the development of atherosclerotic plaques with a lipid-rich core.

The mechanism from elevated plasma levels of triglyceride-rich lipoproteins to development of atherosclerosis involves transfer of these lipoproteins from plasma into the intima, then entrapment in the intima and degradation of the lipoproteins, with final deposition of cholesterol and its esters. It is important to note that triglyceride-rich lipoproteins the size of chylomicrons (>75 nm) do not seem to enter the intima,³⁶ while smaller triglyceride-rich lipoproteins are able to enter.³⁷ There is evidence in both humans and experimental animals that smaller triglyceride-rich lipoproteins are trapped in the arterial intima.^{37 38 39} In contrast to LDL, triglyceride-rich lipoproteins can without prior modification be taken up directly by macrophages to produce foam cells,⁴⁰ the key cell type of the initial atherosclerotic plaque.

Patients on lipid-lowering drugs were excluded from the study, but otherwise the patients took their normal medication (eg, diuretics, antihypertensives) with the fatty meal. However, ß-blockers and thiazide diuretics, both of which are known to potentially increase plasma triglycerides, were not used more commonly in patients with echolucent carotid artery plaques than in other patients (Table 1). An effect of still other types of medication on the outcome of our study is nevertheless difficult to fully exclude.

Very little has been published concerning reproducibility of plaque morphology imaged by ultrasound. In the study by Geroulakos et al,²⁴ in which two different observers evaluated the plaques from 70 carotid arteries and classified them into five groups based on echogenicity and structure, interobserver variability was good (=0.79). In our experience and with the present method, by which 36 carotid arteries were studied, our interobserver variability was also good (=0.61). In no case did the other investigator characterize the echolucent plaques as echo-rich or vice versa. Although more reproducibility studies are needed, it would appear that visual interpretation of carotid artery plaques is reliable. The reproducibility of plasma lipid and lipoprotein measurement during a fat tolerance test seems to be as good as that for fasting levels.⁴¹

The present study suggests that triglyceride-rich lipoproteins may be involved in the development of an echolucent plaque in the carotid artery. The risk of such echolucent lesions requires further investigation, and the effect of treatment of patients with carotid artery disease and a pathological fat tolerance remains to be investigated.

	Selected Abbreviations and Acronyms

 

AUC = area under the curve AUCC = area under the plasma cholesterol curve AUCTG = area under the plasma triglyceride curve BMI = body mass index CR = chylomicron remnants Lp(a) = lipoprotein(a)

	Acknowledgments

 
This study was supported by the Danish Medical and Technical Research Council, the Danish Heart Foundation (Dr Nordestgaard), and the Foundation "Overlæge Johan Boserup og Lise Boserups legat" (Dr Nordestgaard). The authors would like to thank Hanne Damm and Anne Merethe Bengtsen for technical assistance.

	Footnotes

 
Reprint requests to Dr Marie-Louise Moes Grønholdt, Department of Vascular Surgery, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail mlg@ rh.dk.

Presented at the 1996 Cerebral Hemodynamics and Embolism Symposium, Dallas, Tex, January 21-24, 1996.

Received April 11, 1996; revision received July 4, 1996; accepted August 13, 1996.

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