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Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1962-1968
doi: 10.1161/hq1201.099433
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1962.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Elevated C-Reactive Protein Constitutes an Independent Predictor of Advanced Carotid Plaques in Dyslipidemic Subjects

Robert Blackburn; Philippe Giral; Eric Bruckert; Jean-Michel André; Sophie Gonbert; Maguy Bernard; M. John Chapman; Gérard Turpin

From the Service d’Endocrinologie-Métabolisme; INSERM U 551, Dyslipoproteinemia and Atherosclerosis Research Unit, Service de Biochimie and Federated Research Institute, "Heart, Muscle, Vessels," Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Reprint requests to Dr Philippe Giral, Unité de Prévention des Maladies Cardio-Vasculaires, Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail philippe.giral{at}psl.ap-hop-paris.fr


*    Abstract
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 *Abstract
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Inflammation plays a key role in the physiopathology of atherosclerosis. C-reactive protein (CRP) has been found to predict cardiac events in healthy subjects and in patients with coronary heart disease. However, the relationship between CRP and subclinical atherosclerosis is not well established. We examined the potential relationship between CRP and common carotid artery intima-media thickness and carotid plaques in dyslipidemic subjects. Dyslipidemic patients (n=1051) were recruited for the study. All patients had a complete clinical examination and systematically underwent ultrasonographic evaluation of the extracranial carotid arteries on a duplex system. The serum concentration of CRP was measured by using a sensitive immunoradiometric assay. In a univariate model, a strong positive relationship was found between CRP and the severity of carotid stenosis (P<0.0001). In multivariate analysis, the association between CRP and the degree of carotid atherosclerosis remained significant for advanced plaques (P=0.0007) in male subjects only. Significant correlations were found between CRP and body mass index (P<0.0001) and between CRP and other markers associated with the metabolic syndrome. In this large dyslipidemic population, elevated CRP is an independent predictor of advanced carotid plaques in male subjects. Body mass index and other markers of the metabolic syndrome (HDL cholesterol, triglycerides, diabetes, and high blood pressure) are significant determinants of CRP levels in this population.


Key Words: C-reactive protein • carotid plaques • inflammation • body mass index • intima-media thickness


*    Introduction
up arrowTop
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 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Inflammation is a key feature of the development of atherosclerotic plaque.1 Serum levels of C-reactive protein (CRP), a major acute-phase protein, represent a clinical marker of inflammation.2 Recent data have revealed that CRP is associated positively with acute myocardial infarction and sudden cardiac death in patients displaying stable or unstable angina.3–7 Moreover, baseline levels of CRP in healthy subjects have been shown to predict future risk of the development of symptomatic peripheral vascular disease,8 coronary heart disease,9–12 or both.13,14

An association between CRP and the presence and number of stenosed coronary vessels has been documented in coronary atherosclerosis.15–20 With respect to carotid atherosclerosis, 2 studies have shown a positive association between serum CRP levels and the presence of carotid plaques.20,21 In the Bruneck Study (Willeit et al21), a significant relationship between CRP and early nonstenotic atherosclerosis (<=40% narrowing of the lumen) was restricted to univariate analysis. By contrast, in advanced stenotic atherosclerosis (>40% narrowing of the lumen), no association was found. These findings suggest that the relation of risk factors to atherosclerosis may vary according to the severity of the disease. Recently, an association between CRP and common carotid artery (CCA)–intima-media thickness (IMT) has been described in healthy middle-aged women who have ever smoked.22 However, these data remain controversial, inasmuch as Tracy et al23 could not demonstrate an association between CRP and CCA-IMT and carotid plaques in the Cardiovascular Health Study. More recently, Tataru et al15 failed to demonstrate a relationship between CRP and either CCA-IMT or nonstenosing plaques (<50%) in patients with coronary heart disease.

Patients lacking major risk factors for cardiovascular disease (smoking, hypertension, diabetes, and hypercholesterolemia) are considered at low risk. As demonstrated in the Cardiovascular Health Study, CRP and other risk factors are of special value only in patients in which at least 1 of these 4 major risk factors is present.23 Indeed, CRP is a proven risk factor in hypercholesterolemic patients.24 In light of these findings, we focused the present study on a population of dyslipidemic patients.

Our primary objective was to determine whether CRP concentrations were correlated with the presence and extent of atherosclerotic plaques in a large dyslipidemic population. The secondary objective was the analysis of the potential relationship between serum CRP levels and subclinical atherosclerosis in carotid arteries by measurement of CCA-IMT.


*    Methods
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Study Population
A population of 1051 men and women with dyslipidemia were recruited at our specialized Out-Patient Clinic for Dyslipidemia and Cardiovascular Disease; highly sensitive CRP has been analyzed systematically in these patients since January 1, 1999. All patients referred to our Day Care Unit underwent evaluation of their cardiovascular risk with complete clinical examination. Smoking was defined as never, former, or current. No restriction was placed on the period since the cessation of smoking for former smokers. Body mass index (BMI) was defined as the weight (in kilograms) divided by the height (in millimeters squared). All patients underwent blood pressure monitoring of their right and left arms for at least 30 minutes. Subjects who had persistent systolic blood pressure >=140 mm Hg and/or diastolic pressure >=90 mm Hg and/or who were using antihypertensive drugs were considered to be hypertensive. Subjects who reported a medical history of diabetes or use of antidiabetic drugs or who had a plasma glucose level >=7.0 mmol/L were considered to be diabetic. Cardiovascular disease was defined as a history of myocardial infarction, angina, coronary angioplasty or coronary artery bypass, stroke, transient ischemic attack, carotid endarterectomy, intermittent claudication, or peripheral arterial revascularization procedures. Patients were hospitalized in our clinic on the basis of a history of abnormal fasting plasma lipid values: total cholesterol >200 mg/dL, triglycerides >150 mg/dL, or both.

Exclusion criteria were as follows: patients aged <=18 years and >=70 years, creatinine >130 µmol/L, and C-reactive protein >=10 mg/L (this value is commonly used to represent clinically relevant inflammation25,26). In addition, subjects with HDL cholesterol >70 mg/dL and those with LDL cholesterol <160 mg/dL who were not under treatment with lipid-lowering drugs at the time of the checkup were also excluded.

Measurements
Venous blood samples were drawn from each subject after a 12-hour fast. All analyses were performed within 3 hours of blood sampling. Total cholesterol and triglyceride concentrations were determined by an automated enzymatic method (Biomérieux), and HDL cholesterol was determined by an enzymatic procedure after phosphotungstic acid/magnesium chloride precipitation. Fibrinogen, Lp(a), and CRP levels were measured by a latex-enhanced immunonephelometric assay on a BN II analyzer (BNA, Dade Behring).

Carotid Ultrasonography
In the supine position, with the head turned away from the sonographer and the neck extended with mild rotation, each patient systematically underwent ultrasonography of the extracranial carotid arteries by use of a duplex system (ACUSON Sequoia 512). The protocol consisted of the study of the right and left common and internal carotid arteries (including bifurcations) with use of a 7.5-MHz scanning frequency in B-mode and a 3.75-MHz frequency in the pulsed-Doppler mode. The approach was posterior, and the sound beam was set perpendicular to the arterial surface. We used a multifrequency configuration (5 to 8 MHz; access series, mechanical sector scan heads) with a linear array scan head (8L5c) that permitted examination beyond the bifurcation in every case. The IMT was measured 1 cm from the bifurcation.27 Three longitudinal measurements of IMT were completed on the right and left CCAs. We used the mean of the 3 right and left longitudinal CCA-IMT measurements in the analysis. All measurements of CCA-IMT were made at sites free of any discrete plaques. If no lesion was detected, the subject was considered normal. The IMT was defined as the distance between the intimal-luminal interface and the medial-adventitial interface. Plaque was defined as an echogenic structure encroaching the vessel lumen with a distinct area 50% greater than the intimal plus media thickness of neighboring sites.28–30 The measurement was made perpendicular to the length of the vessel wall. Plaques were classified into 2 categories of stenosis severity estimated on the basis of surface area: <40% (early nonstenotic plaques) and >=40% (advanced plaques). The cutoff at 40% stenosis was adopted from a previous study.21,31,32

Statistical Analysis
Mean±SD (SE for logarithmically transformed variables) are given for all continuous variables, and absolute numbers and percentages are given for qualitative variables. Comparisons between the means of 2 groups were made by the Student t test. Comparisons between the 3 classes of carotid stenosis severity were made by using ANOVA and P for trend linear test. Because distributions of CRP, Lp(a), and triglycerides were not normal, we used a logarithmic transformation for calculation of the geometric mean and correlation and regression coefficients. Pearson correlation coefficients for continuous variables were calculated for assessing univariate correlations of log CRP with all variables.

For multivariate linear regression, we first used a stepwise model. All variables that were significantly correlated with CRP in the univariate analysis were included in the model. Fibrinogen was not appropriate for the model because it appears to be at least partially coregulated with CRP through mediators of inflammation. Statistically significant variables selected by the forward stepwise procedure were then included in a new model, and the standard least squares procedures were applied.

A value of P<0.05 was considered significant. We used JMP4 (SAS Institute) software for Windows for all statistical analysis.


*    Results
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 *Results
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The clinical and biological characteristics of the dyslipidemic population are described in Table 1. Our study population consisted of 1051 patients. All patients displayed elevated plasma levels of total cholesterol and/or triglycerides in their history (see inclusion criteria in Methods). Mean plasma levels, which included patients treated with lipid-lowering drugs, were 256 mg/dL for total cholesterol and 159 mg/dL for triglycerides. Overall, 56.2% patients were under drug treatment. Of these patients, 37.0% were treated with statins, 20.4% were treated with fibrates, and 4.3% were treated with cholestyramine. Among the entire study population, 22.5% were treated with cardiovascular drugs, including ACE inhibitors, diuretics, angiotensin receptor antagonists, ß-blockers, and calcium antagonists. CRP varied from 0.1 to 9.9 mg/L (median 1.3 mg/L, interquartile range 0.6 to 2.6 mg/L). CCA-IMT ranged from 0.3 to 1.6 mm. All subjects presented at least 1 major cardiovascular risk factor. Thirty-six percent of the population displayed 2 risk factors, and 136 patients (13%) displayed >=3 risk factors. Analysis by sex (Table 1) revealed that men had higher triglyceride and lower HDL levels than did women. There were more smokers among males, and their systolic blood pressures were higher. In addition, compared with 3.5% of the female patients, 8.6% of the male patients had a history of coronary heart disease (P=0.02). Finally, CCA-IMT was higher in males (0.65 mm versus 0.63 mm in females, P=0.01). However, no difference was found for carotid plaque distribution.


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  		Table 1. Baseline Clinical and Biological Characteristics of the Dyslipidemic Population and by Sex

CRP levels according to cardiovascular status and severity of plaque are presented in Table 2. Distribution of plaque differed significantly between patients with and without cardiovascular disease. Patients with cardiovascular disease have more plaque (79% versus 42% for control patients [without cardiovascular disease], P<10-4) as well as more severe plaque (plaque >=40%, 12% versus 3% for control patients; P<10-4). CRP levels were significantly higher in patients with plaque compared with those with no plaque (1.35±1.05 versus 1.15±1.01, respectively; P<0.01). Furthermore, there is an increase of CRP levels with carotid plaque severity in all patients (P for trend=0.01). The mean CRP level was slightly higher in patients with cardiovascular disease compared with patients without cardiovascular disease (1.43±1.07 versus 1.21±1.03, respectively; P=0.09). As in the whole group, CRP was increased with carotid plaque severity in each subgroup of patients according to cardiovascular status, but because of the small number of patients, the differences between the 3 groups based on plaque severity (or absence thereof) were not significant in patients with cardiovascular disease.


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  		Table 2. Relation of Plasma CRP Levels and Carotid Status in All Patients and in Patients With and Without CVD, According to Carotid Plaque Category

The correlation coefficients between log CRP and continuous variables are indicated in Table 3. There was a significant positive relationship between CRP and CCA-IMT (P=0.003). The most significant association was found between CRP and BMI (P<10-4). Other variables associated with the metabolic syndrome were also significantly associated with CRP, ie, triglycerides, HDL cholesterol, blood pressure, and diabetes. However partial correlation coefficients adjusted for BMI, age, and cardiovascular disease remained significant only for total cholesterol, HDL cholesterol, and triglycerides, whereas correlation with CCA-IMT was lost.


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  		Table 3. Univariate and Partial (Adjusted for Age, BMI, and CVD) Correlation Coefficients Between CRP and Continuous Variables

Mean plasma levels of CRP according to categorical variables are shown in Table 4. Although CRP levels were higher in patients with diabetes or hypertension and in patients receiving cardiovascular treatment or fibrates, adjusted mean CRP levels for age, BMI, and cardiovascular disease were no longer significantly elevated. On the contrary, patients treated with statins exhibited lower levels of CRP, even when adjustments were made for these latter parameters. Women treated with hormonal replacement therapy (HRT) displayed lower levels of CRP than did women not treated with HRT. Among women treated with HRT, 77 (73%) were treated by transdermal estrogens, and their mean CRP levels were lower than those in women receiving oral estrogens (1.02±1.12 versus 1.22±1.26, respectively; P=0.45); this difference was not significant because of the small number in each subgroup and the large SD.


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  		Table 4. Mean Plasma Levels of CRP Stratified by Categorical Variable Status

In multivariate analysis (Table 5), BMI remained the main variable accounting for variance in CRP in the whole group and in men and women. With respect to levels of stenosis severity, when we compared patients with advanced plaques (>=40%) with patients presenting with nonstenotic plaques (<40%) and with no plaques as 1 entity, then plasma levels of CRP in the whole population were clearly higher among patients with plaques exhibiting >=40% stenosis (P=0.03). Because sex was the second most powerful variable and because men seemed to be at higher cardiovascular risk than women, we evaluated these data in each population. For men, the presence of advanced plaque was highly associated with elevated plasma CRP levels (P<0.005). By contrast, no relationship was detected in women.


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  		Table 5. Results of Multivariate Regression Analysis for Log CRP


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In the present cross-sectional study, we evaluated the relationship between CRP and the degree of carotid atherosclerosis in a large dyslipidemic population, which included patients presenting with symptomatic cardiovascular disease. First, we detected a highly significant association between plasma levels of CRP and the severity of carotid stenosis in univariate analysis. A significant relationship was also detected when CRP was compared with the presence of carotid plaque (P=0.006). In multivariate analysis, we demonstrated that CRP levels were higher among patients with advanced plaques with >=40% narrowing of the lumen compared with dyslipidemic subjects with <40% stenosis (P=0.02). However, this association was significant in men only (Table 5).

Two studies have detected a relationship between CRP and carotid plaque.20,21 In the Bruneck Study,21 this association was observed for small plaques only in univariate analysis. Heinrich et al20 demonstrated an association between CRP and the presence of plaque but failed to show a difference between severity of plaque stenosis. The present study demonstrates that advanced plaques are related to elevated plasma levels of high-sensitivity (hs)-CRP in a dyslipidemic male population. When we compared men and women, men were at higher cardiovascular risk. Systolic blood pressure, triglycerides, and cigarette smoking remained significant in the multivariate analysis and were higher among male subjects, consistent with the finding that this relationship was observed in males only. Furthermore, HRT may represent a confounding factor as a consequence of the differential effect that is due to the route of administration. Indeed, it has recently been demonstrated that transdermal estradiol does not modify the CRP level in contrast to the oral route, which is associated with an increase in CRP levels.33

When considered together, data in the present study support the hypothesis that inflammatory processes in the vessel wall participate in atherogenesis. Furthermore, our findings demonstrate an elevation in the inflammatory state according to the degree of stenosed plaques. The fact that 12% of our population presented with a symptomatic form of cardiovascular disease and was in secondary prevention did not modify the relationship between CRP and plaque status. Even though our patients with cardiovascular disease displayed slightly higher CRP levels than did patients without cardiovascular disease, this did not change the relationship between CRP and plaque gravity. Finally, multivariate analysis eliminated cardiovascular disease as a significant variable but maintained the significant relationship of plaque severity in relation to CRP levels.

As reported elsewhere,22,34,35 measures of obesity (BMI), markers of abdominal obesity (waist-to-hip ratio), and other variables associated with the metabolic syndrome (triglycerides, HDL cholesterol, high blood pressure, and diabetes) are strongly associated with CRP. Indeed, in the present study, BMI accounted for a much larger proportion of the variance in CRP than did carotid plaque. Thus, these results confirm the subclinical inflammatory state found in the metabolic syndrome, which in turn may be accounted for by production of interleukin-6 by adipose tissue.36 Furthermore (and as shown in Table 3), LDL cholesterol levels were not associated with CRP. By contrast, CRP has been found to be related to LDL cholesterol in other studies.37,38 However, because our dyslipidemic population involves a relatively narrow range of LDL cholesterol values, it may readily be realized that such a group is not the most appropriate in which to detect a relationship between lipid parameters and serum CRP levels.

The present study population was diversified. Dyslipidemic men and women over a large range of ages were included in the analysis. Patients with HDL cholesterol >70 mg/dL and LDL cholesterol <160 mg/dL who were not under treatment with lipid-lowering drugs were excluded to ensure that our population was clearly dyslipidemic. They all presented at least 1 of the 4 major risk factors, and so they were at least at moderate risk of cardiovascular disease. Therefore, our results may not apply to all populations. Also, the large population included in the trial allowed us to adjust for several variables. Indeed, we inserted all variables that might explain the association between CRP and carotid atherosclerosis, including treatment with lipid-lowering drugs, in our final analysis. Statins were a powerful variable influencing CRP levels. Clearly, CRP was lower among patients who were under treatment with statins (Table 4), a finding that corroborates recent studies showing significantly reduced levels of CRP in patients treated with statins.39,40 A relatively small number of patients displayed plaques with >=40% stenosis. However, the relationship that we found was statistically significant. The small number of patients with advanced plaques may be explained by the mean age of our population (51 years). Finally, despite the cross-sectional design of the present study, we were able to confirm all variables (including BMI, triglycerides, HDL cholesterol, high blood pressure, and diabetes) that have been shown to be associated with CRP levels in earlier studies.22,34,35

Subclinical carotid atherosclerosis measurement has been widely used to evaluate atherosclerosis.41–45 Increased CCA-IMT and carotid plaques are associated with an increased risk of myocardial infarction,46–50 stroke,48–50 and death.50 In the present study, IMT was measured on CCA segments free of any focal atherosclerotic lesion, and the mean rather than the maximum value of 3 measurements was used. IMT measurement has proven to be a simple noninvasive technique that is highly reproducible.51,52 Methods used to measure plaques have been validated elsewhere.28–30 Plaques were defined by wall surface. The different degrees of stenosis severity chosen in our trial have been corroborated in the Bruneck Study.21,31,32 For the measurement of hs-CRP, we used a standardized kit that has been shown to be accurate and reproducible.13,53

In conclusion, the present cross-sectional study has revealed that elevated levels of hs-CRP are positively correlated with advanced carotid plaques in a large population of dyslipidemic patients. Furthermore, we confirmed the strong association between CRP, obesity, and other variables included in or intimately associated with the metabolic syndrome.


*    Acknowledgments
 
Dr Blackburn was supported by La Fondation Québécoise pour le Progrès de la Médecine Interne and by Le Collège Royal des Médecins et Chirurgiens du Canada. We are indebted to J.P. Suquet for management of our patient database.

Received May 3, 2001; accepted September 6, 2001.


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 up arrowIntroduction
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 up arrowResults
 up arrowDiscussion
 *References
 

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