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Figure 1.
Distribution of high-sensitivity C-reactive protein (hs-CRP) concentration in the study population.

Distribution of high-sensitivity C-reactive protein (hs-CRP) concentration in the study population.

Figure 2.
Association (adjusted odds ratios and 95% confidence intervals) between high-sensitivity C-reactive protein and aortic plaques in the total population and subjects free of clinical cardiovascular disease (CVD).

Association (adjusted odds ratios and 95% confidence intervals) between high-sensitivity C-reactive protein and aortic plaques in the total population and subjects free of clinical cardiovascular disease (CVD).

Table 1. 
Clinical and Laboratory Variables Associated With the Presence and Severity of Aortic Plaques*
Clinical and Laboratory Variables Associated With the Presence and Severity of Aortic Plaques*
Table 2. 
Multivariate Predictors of Aortic Plaques*
Multivariate Predictors of Aortic Plaques*
Table 3. 
Blood Cell Counts, Fibrinogen, hs-CRP, and Aortic Plaques*
Blood Cell Counts, Fibrinogen, hs-CRP, and Aortic Plaques*
Table 4. 
Blood Counts, Fibrinogen, hs-CRP, and Adjusted Odds Ratios of Aortic Atherosclerosis*
Blood Counts, Fibrinogen, hs-CRP, and Adjusted Odds Ratios of Aortic Atherosclerosis*
1.
Ross  R Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340115- 126
PubMedArticle
2.
Ridker  PMCushman  MStampfer  MJTracy  RPHennekens  CH Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336973- 979
PubMedArticle
3.
Tracy  RPLemaitre  RNPsaty  BM  et al.  Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;171121- 1127
PubMedArticle
4.
Ridker  PMHennekens  CHBuring  JERifai  N C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342836- 843
PubMedArticle
5.
Redberg  RFRifai  NGee  LRidker  PM Lack of association of C-reactive protein and coronary calcium by electron beam computed tomography in postmenopausal women: implications for coronary artery disease screening. J Am Coll Cardiol. 2000;3639- 43
PubMedArticle
6.
van der Wal  ACBecker  AEvan der Loos  CMDas  PK Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;8936- 44
PubMedArticle
7.
Pasceri  VWillerson  JTYeh  ET Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;1022165- 2168
PubMedArticle
8.
Meissner  IWhisnant  JPKhandheria  BK  et al.  Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study: Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc. 1999;74862- 869
PubMedArticle
9.
Agmon  YKhandheria  BKMeissner  I  et al.  Independent association of high blood pressure and aortic atherosclerosis: a population-based study. Circulation. 2000;1022087- 2093
PubMedArticle
10.
Agmon  YKhandheria  BKMeissner  I  et al.  Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? insights from a population-based study. J Am Coll Cardiol. 2001;38827- 834
PubMedArticle
11.
French Study of Aortic Plaques in Stroke Group, Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med. 1996;3341216- 1221
PubMedArticle
12.
Rohde  LEHennekens  CHRidker  PM Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol. 1999;841018- 1022
PubMedArticle
13.
Hak  AEStehouwer  CDBots  ML  et al.  Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999;191986- 1991
PubMedArticle
14.
Elkind  MSSciacca  RBoden-Albala  BHomma  SDi Tullio  MR Leukocyte count is associated with aortic arch plaque thickness. Stroke. 2002;332587- 2592
PubMedArticle
15.
Tribouilloy  CPeltier  MColas  L  et al.  Fibrinogen is an independent marker for thoracic aortic atherosclerosis. Am J Cardiol. 1998;81321- 326
PubMedArticle
16.
Tracy  RPPsaty  BMMacy  E  et al.  Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997;172167- 2176
PubMedArticle
17.
Folsom  ARPankow  JSTracy  RP  et al.  Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol. 2001;88112- 117
PubMedArticle
18.
Wang  TJLarson  MGLevy  D  et al.  C-reactive protein is associated with subclinical epicardial coronary calcification in men and women: the Framingham Heart Study. Circulation. 2002;1061189- 1191
PubMedArticle
19.
Hunt  MEO'Malley  PGVernalis  MNFeuerstein  IMTaylor  AJ C-reactive protein is not associated with the presence or extent of calcified subclinical atherosclerosis. Am Heart J. 2001;141206- 210
PubMedArticle
20.
van der Meer  IMde Maat  MPBots  ML  et al.  Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study. Arterioscler Thromb Vasc Biol. 2002;22838- 842
PubMedArticle
21.
Wang  TJNam  BHWilson  PW  et al.  Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2002;221662- 1667
PubMedArticle
22.
Vaduganathan  PEwton  ANagueh  SFWeilbaecher  DGSafi  HJZoghbi  WA Pathologic correlates of aortic plaques, thrombi and mobile "aortic debris" imaged in vivo with transesophageal echocardiography. J Am Coll Cardiol. 1997;30357- 363
PubMedArticle
23.
Byington  RPDavis  BRPlehn  JF  et al.  Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001;103387- 392
PubMedArticle
24.
Bloomfield Rubins  HDavenport  JBabikian  V  et al.  Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation. 2001;1032828- 2833
PubMedArticle
25.
Ridker  PMRifai  NPfeffer  MASacks  FBraunwald  ECholesterol and Recurrent Events (CARE) Investigators, Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999;100230- 235
PubMedArticle
26.
Ridker  PMRifai  NClearfield  M  et al.  Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;3441959- 1965
PubMedArticle
Original Investigation
September 13, 2004

C-Reactive Protein and Atherosclerosis of the Thoracic AortaA Population-Based Transesophageal Echocardiographic Study

Author Affiliations

From the Division of Cardiovascular Diseases and Internal Medicine (Drs Agmon, Khandheria, Seward, and Tajik) and the Departments of Neurology (Drs Meissner and Wiebers), Health Sciences Research (Mss Petterson and Christianson and Drs O'Fallon and Whisnant), and Laboratory Medicine and Pathology (Dr McConnell), Mayo Clinic, Rochester, Minn. Dr Agmon is now with the Department of Cardiology, Rambam Medical Center, Haifa, Israel. The authors have no relevant financial interest in this article.

Arch Intern Med. 2004;164(16):1781-1787. doi:10.1001/archinte.164.16.1781
Abstract

Background  An association between systemic inflammatory markers and the presence and severity of atherosclerotic plaques has not been demonstrated in a nonselected population. The purpose of this study was to examine the association of inflammatory markers with aortic atherosclerotic plaques in a sample of the general population and in a subgroup free of clinical vascular disease.

Methods  Transesophageal echocardiography was performed in 386 subjects (median age, 66 years; 53% men). We examined the association between systemic inflammatory markers and aortic atherosclerotic plaques.

Results  Aortic plaques were present in 267 subjects (69%). Plaques at least 4 and 6 mm thick and mobile debris were present in 114, 41, and 20 subjects, respectively. High-sensitivity C-reactive protein (hs-CRP) level was associated with the presence of aortic plaques, adjusting for age, sex, smoking status, and additional atherosclerosis risk factors. Among subjects with plaques, hs-CRP level was independently associated with plaques at least 6 mm thick; similar trends were observed for the associations of hs-CRP level with plaques at least 4 mm thick and mobile debris. In subjects with aortic plaques who were free of clinically apparent coronary artery or cerebrovascular disease, hs-CRP level was independently associated with plaques at least 6 mm thick.

Conclusions  Level of hs-CRP is independently associated with the presence and severity of aortic atherosclerotic plaques. These observations establish the association of systemic inflammation with anatomically defined atherosclerosis in the general population.

Inflammation has a major role in the pathogenesis of atherosclerosis.1 The association of various markers of systemic inflammation with clinical cardiovascular events has been well demonstrated in numerous populations, including subjects apparently free of cardiovascular disease.24 This association is independent of other atherosclerosis risk factors, including plasma lipid levels,4 and enables cardiovascular risk to be better defined.

It has been hypothesized that the association between markers of systemic inflammation and cardiovascular events reflects the underlying atherosclerotic plaque burden,5 specifically the presence of unstable, rupture-prone plaques.6 Alternatively, these associations with atherothrombotic complications may result directly from the proinflammatory7 or prothrombotic (eg, fibrinogen) effects of several acute-phase reactants.

The Stroke Prevention: Assessment of Risk in a Community (SPARC) study is a population-based study funded by the National Institutes of Health, Bethesda, Md. The study is designed to evaluate the prevalence of risk factors for stroke in the population of Olmsted County, Minnesota.8 Study participants underwent evaluation with multiple modalities, including transesophageal echocardiography (TEE).9 The objective of our present analysis was to examine the association of systemic inflammatory markers with aortic atherosclerotic plaques in a sample of the general population and in a subgroup of subjects free of clinical vascular disease.

METHODS
STUDY POPULATION

The study design and initial results of the first phase of the SPARC study have been described in detail.8,9 In brief, the original study cohort consisted of 581 subjects, an age- and sex-stratified random sample of the Olmsted County population 45 years and older. Approximately 4 to 5 years after the initial evaluation (median, 4.6 years; range, 3.8-5.4 years), eligible participants were enrolled in the second phase of the SPARC study. Of 504 subjects eligible for the second study phase (excluding 3 subjects lost to follow-up, 54 who died, and 20 with severe medical disabilities precluding participation), 392 (78%) agreed to participate. Transesophageal echocardiography was repeated successfully in 388 subjects (99% of the participants in the second phase of the SPARC study),10 of whom 386 were included in the current analysis (2 subjects were excluded from analysis because of incomplete echocardiographic data). The median age of the study participants was 66 years (range, 51-101 years); 53% were men. The study was approved by the Mayo Clinic Institutional Review Board, Rochester, Minn. Written informed consent was obtained from all participants.

CLINICAL AND LABORATORY DATA

Data on clinical cardiovascular risk factors and clinical coronary artery and cerebrovascular disease were collected by interviews and abstracting of medical records (at Mayo Clinic and Olmsted Medical Center, the 2 primary health care providers in Olmsted County). Blood pressure was measured during an office interview related to the SPARC study. Two sitting blood pressure measurements were taken 5 to 10 minutes apart and averaged. Pulse pressure was defined as the difference between the mean systolic and diastolic measurements. Treatment of hypertension or hyperlipidemia was defined as the use of antihypertensive or lipid-lowering drugs, respectively (self-reported during interview).

Fasting blood samples were collected (on the day TEE was performed for 97% of participants and within 20 days of TEE for all participants). With the use of standard commercially available assays, samples were analyzed for (1) plasma lipid levels (measurements of total cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, and apolipoprotein A-I and B levels and calculation of low-density lipoprotein [LDL] cholesterol level); (2) homocysteine level; (3) blood cell counts (including leukocyte differential count); (4) fibrinogen level; and (5) high-sensitivity C-reactive protein (hs-CRP) level, measured with a high-sensitivity latex-enhanced immunotubidimetric assay (Kamiya Biomedical Co, Seattle, Wash).

TRANSESOPHAGEAL ECHOCARDIOGRAPHY

Transesophageal echocardiography was performed using commercially available ultrasound instruments equipped with multiplane probes. Local pharyngeal anesthesia and intravenous sedation (midazolam hydrochloride and meperidine hydrochloride) were used as clinically indicated.

The 3 segments of the thoracic aorta (ascending aorta, aortic arch, and descending thoracic aorta) were visualized in short- and long-axis views with high-frequency (7-MHz) ultrasonographic imaging. Atherosclerotic plaques were defined as irregular intimal thickening (≥2 mm thick) with increased echogenicity. The presence of plaques of any degree in any location within the thoracic aorta was determined. Among subjects with plaques, maximal plaque thickness and the presence of mobile debris in any aortic segment were determined. In this analysis, plaque thickness was arbitrarily dichotomized at 4 mm11 and 6 mm (detected in approximately 10% of the study population).

STATISTICAL ANALYSIS

We summarized continuous data as medians and interquartile (25-75 percentile) ranges and categorical data as percentages. For continuous data, groups were compared by the unpaired t test (normal data) or Wilcoxon rank sum test (nonnormal data). For categorical data, groups were compared by the χ2 test or Fisher exact test, as appropriate. We calculated Spearman correlation coefficients to examine the correlations between continuous variables.

We performed 2 separate series of multivariate analyses. The first series of analyses compared subjects with aortic plaques (of any degree) with subjects without plaques. The second series of analyses, done in the subgroup of subjects with aortic plaques, compared subjects with more severe forms of plaques (defined by plaque thickness or presence of mobile debris) with subjects with plaques of lesser severity. We used logistic regression to assess the impact of age, sex, clinical and laboratory atherosclerosis risk factors, treatment variables, and inflammatory markers on the odds of aortic plaques (proportion with any aortic plaques divided by proportion without plaques). Among subjects with plaques, we assessed the odds of plaques of at least 4 mm (proportion with plaques ≥4 mm divided by proportion with plaques <4 mm), plaques of at least 6 mm (proportion with plaques ≥6 mm divided by proportion with plaques <6 mm), and mobile debris (proportion with mobile debris divided by proportion without debris). Variables with skewed distributions were logarithmically transformed to normalize the data before assessing them in the logistic regression models.

Initially, with the use of stepwise logistic regression, atherosclerosis risk factor models were developed for each plaque variable. Clinical and laboratory atherosclerosis risk factors, summarized in Table 1 (not including clinical coronary artery and cerebrovascular disease variables), competed for entry into the models. All stepwise logistic modeling was adjusted for age. Sex was forced into models with a large number of subjects with the plaque variables (models of any aortic plaques and plaques ≥4 mm). Smoking was forced into all models because of its association with increased levels of systemic inflammatory markers.12 Smoking was modeled as current and past (vs never) for models with a large number of subjects with the plaque variables and as ever vs never for models with a small number of subjects with the plaque variables (models of plaques ≥6 mm and mobile debris). The P value to enter and leave the stepwise models was .05. When the list of independent variables was finalized, all 2-way interactions of the variables were analyzed for each of the models.

Subsequently, we used these logistic regression models to examine separately the associations of each individual inflammatory variable with each plaque variable, adjusting for age, smoking, and additional noninflammatory risk factors included in the stepwise models. These associations were assessed in the total study population and, subsequently, in the subgroup of subjects without clinically evident coronary artery disease (previous myocardial infarction, angina pectoris, coronary artery bypass graft surgery, or percutaneous coronary angioplasty) or cerebrovascular disease (previous ischemic stroke, transient ischemic attack, or carotid endarterectomy).

RESULTS

Aortic plaques of any degree were present in 267 subjects (69% of the study population). Plaques were uncommon in the ascending aorta (23 subjects [6%]), but common in the aortic arch (244 subjects [63%]) and descending thoracic aorta (211 subjects [55%]). Plaques at least 4 mm thick, plaques at least 6 mm thick, and mobile debris (in any aortic segment) were present in 114 (30%), 41 (11%), and 20 subjects (5%), respectively. Plaque thickness was significantly greater in subjects with mobile debris than in those without debris (median plaque thickness, 6 vs 3 mm, respectively; P<.001).

The clinical and laboratory atherosclerosis risk factors in subjects with various degrees of aortic plaques are presented in Table 1. Results of the stepwise multivariate logistic modeling assessing the impact of noninflammatory atherosclerosis risk factors on the odds of aortic plaques are summarized in Table 2. Age was strongly associated with the presence of aortic plaques (of any degree) and, within the subgroup with plaques, was associated with thick plaques (≥4 and ≥6 mm thick) and mobile debris. Smoking and higher pulse pressure were associated with plaques of any degree and of at least 4 mm; higher body mass index was associated with plaques of at least 4 mm and with mobile debris.

Dyslipidemia was significantly associated with the presence and severity of aortic plaques. Lipid-lowering treatment was associated more strongly with the presence of plaques (of any degree) than the actual measurements of lipid levels. Among subjects with plaques, lower HDL cholesterol and apolipoprotein A-I (an HDL-associated apolipoprotein) levels were the lipid measures most strongly associated with thick plaques (≥6 and ≥4 mm thick, respectively), and total cholesterol level was the lipid measure most strongly associated with mobile debris. There were no significant interactions between the final variables in all the risk factor models presented in Table 2.

The values of inflammatory variables in subjects with various degrees of aortic plaques are shown in Table 3. Table 4 summarizes the associations between these variables and aortic plaques, adjusting for the risk factors in the respective multivariate logistic models presented in Table 2. The distribution of hs-CRP concentration in the population is shown in Figure 1. Because of its skewed distribution, hs-CRP values were logarithmically transformed, achieving near-normal distribution,12 and odds ratios (ORs) were estimated per 2-fold increase in hs-CRP concentration (Table 4 and Figure 2). In the total population, hs-CRP level was independently associated with the presence of aortic plaques (OR, 1.25 per 2-fold increase in hs-CRP level), adjusting for age, sex, smoking status, and additional atherosclerosis risk factors defined in the risk factor model. Among the subgroup with plaques, hs-CRP level was independently associated with thick (≥6 mm) plaques (OR, 1.36 per 2-fold increase in hs-CRP level), adjusting for age, smoking, and additional atherosclerosis risk factors. These associations remained significant (P = .04 for any plaques and P = .03 for plaques ≥6 mm) after additional adjustment for body mass index, which is a major determinant of hs-CRP concentration.13 Similar trends, which did not reach statistical significance, were noted for the associations of hs-CRP level with plaques at least 4 mm thick and mobile debris among the subgroup with plaques.

Two hundred ninety-seven subjects (77%) were free of clinical coronary artery and cerebrovascular disease. The associations between hs-CRP level and aortic plaques in this subgroup are presented in Figure 2. In the subgroup of apparently healthy subjects who had aortic plaques, the odds of plaques at least 6 mm thick were almost 2-fold greater per 2-fold increase in hs-CRP level (OR, 1.92 per 2-fold increase in hs-CRP level; 95% confidence interval, 1.26-2.93; P = .003), adjusting for age, smoking, and additional atherosclerosis risk factors.

Most of the correlations of blood cell counts and fibrinogen with hs-CRP level were statistically significant, albeit weak (all correlation coefficients <0.4). None of these additional inflammatory variables were independently associated with the presence or severity of aortic plaques after adjusting for the risk factors in the respective multivariate logistic models (Table 4).

COMMENT

Our population-based study demonstrates the association of plasma hs-CRP level, predominantly within the reference range, with aortic atherosclerotic plaques. High-sensitivity CRP level was associated with the presence of aortic plaques and, among subjects with atherosclerosis, it was associated with more severe plaques. These associations were independent of age, smoking, and additional atherosclerosis risk factors (including lipid levels) and were apparent in the total study population, a sample of the general population, and the subgroup free of clinical cardiovascular disease. We did not detect any association between other markers of inflammation, such as leukocyte count14 or fibrinogen level,15 and aortic plaques, a finding concordant with clinical studies that have shown a stronger association of hs-CRP level with cardiovascular events, compared with other inflammatory markers.4

Although the association between systemic inflammatory markers and clinical cardiovascular events is well established in multiple populations,24 current data on the association of these markers with atherosclerotic plaques (ie, anatomically defined atherosclerosis) in nonselected populations are less conclusive. In healthy middle-aged women, ultrasonographically measured carotid artery intima-medial thickness was associated with hs-CRP levels, although this association was weak and confined to ever-smokers.13 No association between hs-CRP level and carotid artery intima-medial thickness was noted in a sample of apparently healthy elderly subjects participating in the Cardiovascular Health Study16 or in subjects participating in a large cross-sectional family-based study.17 Recently, an association between hs-CRP level and coronary artery calcification, a surrogate of coronary artery atherosclerosis, has been demonstrated in the Framingham Offspring Study,18 but this association was of borderline significance in women (after adjusting for body mass index). Two other studies failed to demonstrate an association between hs-CRP level and coronary calcification in asymptomatic postmenopausal women5 and in healthy young men.19

Recently, an association between hs-CRP level and atherosclerotic plaques (demonstrated directly with ultrasonography), in addition to its association with intima-medial thickness, has been observed in 2 population-based studies. High-sensitivity CRP level was associated with the extent (presence of plaques in multiple carotid segments) but not the severity of carotid atherosclerosis in the Rotterdam Study,20 but the role of dyslipidemia as a possible confounder in the association between hs-CRP level and carotid plaques was not examined in that study. High-sensitivity CRP level was associated with relatively mild carotid atherosclerosis in the Framingham Offspring Study,21 an association that was not significant in men after multivariate adjustment. To the best of our knowledge, our study is the first to demonstrate an association between hs-CRP level and the presence and complexity of atherosclerotic plaques in a population-based setting, an association that was independent of other risk factors for aortic atherosclerosis (including lipid risk factors). With high-resolution real-time TEE imaging, the full spectrum of aortic atherosclerotic disease was demonstrable, from minor plaques to protruding plaques and mobile debris. Previous studies were limited by their measurements of carotid intima-medial thickening (an early preplaque atherosclerosis-related lesion), relatively mild atherosclerotic lesions, or coronary calcification (an indirect surrogate of coronary plaques).

The role of dyslipidemia as a risk factor for aortic atherosclerosis has not been well established.9 In our present study, treatment with lipid-lowering drugs was strongly associated with the presence of aortic plaques, a finding consistent with a confounding effect of lipid-lowering therapy. Statins were the major drugs used as lipid-lowering therapy in our study population (88% of treated subjects). Thus, it is likely that lipid-lowering therapy was a marker of high LDL cholesterol level before therapy, and the association of lipid-lowering treatment may be a surrogate of the association between increased LDL cholesterol levels and aortic plaques. Total cholesterol level, which is quantitatively determined primarily by LDL cholesterol level, was independently associated with mobile atherosclerotic debris, the echocardiographic hallmark of ruptured aortic plaques with superimposed thrombosis,22 suggesting that high LDL cholesterol levels may also predispose to aortic plaque rupture. Interestingly, levels of HDL cholesterol and apolipoprotein A-I, an HDL-associated apolipoprotein, were negatively associated with thick (protruding) aortic plaques, which are associated with clinical cardiovascular events.11 Together these observations support the results of clinical trials demonstrating a decrease in cerebrovascular events with both statins23 and therapy to raise HDL cholesterol levels (gemfibrozil).24 Recent studies have shown that statins decrease hs-CRP levels25 and suggest that some of the beneficial clinical effects of statin therapy may be related to its anti-inflammatory effect.26 Although our study was not designed to address this issue, we did not detect any interaction among lipid-lowering therapy (primarily statins), hs-CRP levels, and their association with the presence of aortic plaques, suggesting that lipid-lowering therapy did not substantially affect our study results.

Complex aortic plaques are associated with cerebral and peripheral thromboembolic events and are high-risk markers of nonembolic cardiovascular disease.11 Our data support the hypothesis that systemic inflammatory markers are markers of severe atherosclerosis and are presumably associated with cardiovascular events through their association with underlying high-risk plaques. Additional direct proinflammatory or prothrombotic effects of acute-phase reactants on atherosclerotic plaques cannot be excluded by our results.

CONCLUSIONS

Our study demonstrates that hs-CRP level is significantly associated with the presence and severity of atherosclerotic plaques in the general population, an association that is independent of other risk factors. These observations provide a missing anatomical link for the apparent association between systemic inflammatory markers and clinical cardiovascular events.

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Article Information

Correspondence: Bijoy K. Khandheria, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (khandheria@mayo.edu).

Accepted for publication September 30, 2003.

This study was supported in part by research grant NS-06663 from the National Institute of Neurological Disorders and Stroke, Bethesda, Md.

This study was presented at the 73rd Scientific Sessions of the American Heart Association; November 13, 2000; New Orleans, La; and published as an abstract in Agmon Y, Khandheria BK, Meissner I, et al. Serum C-reactive protein levels are associated with the presence and severity of atherosclerosis of the thoracic aorta: a population-based transesophageal echocardiographic study [abstract]. Circulation. 2000;102(suppl 2):II-43.

References
1.
Ross  R Atherosclerosis: an inflammatory disease. N Engl J Med. 1999;340115- 126
PubMedArticle
2.
Ridker  PMCushman  MStampfer  MJTracy  RPHennekens  CH Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336973- 979
PubMedArticle
3.
Tracy  RPLemaitre  RNPsaty  BM  et al.  Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;171121- 1127
PubMedArticle
4.
Ridker  PMHennekens  CHBuring  JERifai  N C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342836- 843
PubMedArticle
5.
Redberg  RFRifai  NGee  LRidker  PM Lack of association of C-reactive protein and coronary calcium by electron beam computed tomography in postmenopausal women: implications for coronary artery disease screening. J Am Coll Cardiol. 2000;3639- 43
PubMedArticle
6.
van der Wal  ACBecker  AEvan der Loos  CMDas  PK Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;8936- 44
PubMedArticle
7.
Pasceri  VWillerson  JTYeh  ET Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;1022165- 2168
PubMedArticle
8.
Meissner  IWhisnant  JPKhandheria  BK  et al.  Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study: Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc. 1999;74862- 869
PubMedArticle
9.
Agmon  YKhandheria  BKMeissner  I  et al.  Independent association of high blood pressure and aortic atherosclerosis: a population-based study. Circulation. 2000;1022087- 2093
PubMedArticle
10.
Agmon  YKhandheria  BKMeissner  I  et al.  Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? insights from a population-based study. J Am Coll Cardiol. 2001;38827- 834
PubMedArticle
11.
French Study of Aortic Plaques in Stroke Group, Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med. 1996;3341216- 1221
PubMedArticle
12.
Rohde  LEHennekens  CHRidker  PM Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. Am J Cardiol. 1999;841018- 1022
PubMedArticle
13.
Hak  AEStehouwer  CDBots  ML  et al.  Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999;191986- 1991
PubMedArticle
14.
Elkind  MSSciacca  RBoden-Albala  BHomma  SDi Tullio  MR Leukocyte count is associated with aortic arch plaque thickness. Stroke. 2002;332587- 2592
PubMedArticle
15.
Tribouilloy  CPeltier  MColas  L  et al.  Fibrinogen is an independent marker for thoracic aortic atherosclerosis. Am J Cardiol. 1998;81321- 326
PubMedArticle
16.
Tracy  RPPsaty  BMMacy  E  et al.  Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997;172167- 2176
PubMedArticle
17.
Folsom  ARPankow  JSTracy  RP  et al.  Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol. 2001;88112- 117
PubMedArticle
18.
Wang  TJLarson  MGLevy  D  et al.  C-reactive protein is associated with subclinical epicardial coronary calcification in men and women: the Framingham Heart Study. Circulation. 2002;1061189- 1191
PubMedArticle
19.
Hunt  MEO'Malley  PGVernalis  MNFeuerstein  IMTaylor  AJ C-reactive protein is not associated with the presence or extent of calcified subclinical atherosclerosis. Am Heart J. 2001;141206- 210
PubMedArticle
20.
van der Meer  IMde Maat  MPBots  ML  et al.  Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study. Arterioscler Thromb Vasc Biol. 2002;22838- 842
PubMedArticle
21.
Wang  TJNam  BHWilson  PW  et al.  Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2002;221662- 1667
PubMedArticle
22.
Vaduganathan  PEwton  ANagueh  SFWeilbaecher  DGSafi  HJZoghbi  WA Pathologic correlates of aortic plaques, thrombi and mobile "aortic debris" imaged in vivo with transesophageal echocardiography. J Am Coll Cardiol. 1997;30357- 363
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