| | Intraplaque hemorrhage assessed by high-resolution magnetic resonance imaging and C-reactive protein in carotid atherosclerosisReceived 15 March 2007; accepted 3 July 2007. published online 08 October 2007. BackgroundCarotid intraplaque hemorrhage is a marker of atheroma instability. Noninvasive assessment of bleeding can be performed by high-resolution magnetic resonance imaging (MRI), but its association with inflammatory markers has not been clearly demonstrated. MethodsWe evaluated consecutive carotid endarterectomy patients that underwent high-resolution MRI, independent evaluation of neurologic symptoms, C-reactive protein measurement, and histologic analysis. Intraplaque hemorrhage was determined by the presence of a hyperintense MRI signal (T1-weighted sequence). ResultsThe study included 70 predominantly male (66%) and hypertensive (89%) patients (89%) aged 66 ± 9 years old. MR angiography identified 15 patients (21.5%) with stenosis between 50% and 69%, 15 (21.5%) with stenosis between 70% and 90%, and 40 (57%) with stenosis >90%. High-resolution MRI depicted a hyperintense signal suggestive of intraplaque bleeding in 45 subjects (64%). All patients who had had transient ischemic attacks >90 days before the surgery showed a hyperintense signal on MRI (P = .007). Age, gender, traditional cardiovascular risk factors, and history of myocardial infarction or peripheral arterial disease were similar in patients with or without signs of intraplaque bleeding on MRI. There was excellent agreement between acute or recent hemorrhage on histologic and MRI findings (κ coefficient, 0.91; 95% confidence interval, 0.81 to 1.00). Only one of 45 patients (2%) with a hyperintense signal on MRI did not have acute or recent hemorrhage in the histologic analysis (P < .001). High-sensitivity C-reactive protein levels were similar for different degrees of carotid stenosis as assessed by MR angiography, but they were significantly higher in clinically unstable patients (P = .006) and in those with a positive hyperintense MRI signal (P = .01). In an aggregated analysis of neurologic symptoms and MRI findings, we found a progressive increase of high-sensitivity C-reactive protein levels (P = .02). ConclusionsIntraplaque hemorrhage evaluated by MRI identified neurologically unstable patients with increased levels of high-sensitivity C-reactive protein regardless of the degree of carotid stenosis. Kenneth Ouriel, MD, Review Articles Section Editor Cerebral vascular disease is a major cause of morbidity and mortality in the adult population.1, 2 Atherothrombosis of the carotid bifurcation is responsible for approximately 30% of cerebral ischemic episodes, and carotid endarterectomy is considered the treatment of choice for selected patients.3 Although current indications for carotid endarterectomy are based on luminal stenosis, some clinical and histopathologic evidence indicates that acute vascular events occur mostly due to the instability of vulnerable plaques.4, 5 Indeed, atheroma vulnerability is not directly related to the occlusive nature of the atheroma, depending instead on other factors, such as local and systemic immunoinflammatory responses, structural imbalance of the extracellular matrix components, intraplaque hemorrhage, rupture of the fibrous cap, and thrombogenesis.6, 7, 8 High-sensitivity C-reactive protein (hs-CRP) is the prototype serum inflammatory marker of coronary and carotid artery atherosclerotic disease.9, 10, 11 Although no definite association has been found between hs-CRP and initial carotid atherosclerosis, as assessed by intimal-medial thickness,12 high levels of hs-CRP have been associated with the presence of extracranial atherosclerotic disease13 and the prediction of cerebral ischemic events in the general population.14 The role of hs-CRP on the events that lead to clinical instability of carotid atherosclerotic disease, however, is much less clear.15 Detailed in vivo morphologic characterization of the carotid atheroma has greatly improved in the last few years, particularly because of advances in noninvasive imaging techniques.16 High-resolution magnetic resonance imaging (MRI) allows in vivo imaging of areas of hemorrhage in the medial layer of carotid artery plaques by the identification of segments with intense brightness (described as a hyperintense signal) using specific MRI protocols.17, 18 Although the hyperintense signal on carotid MRI has an adequate correlation with clinical and histologic findings,19, 20 its association with serum inflammatory markers has not yet been completely clarified. In this prospective study, we evaluated consecutive carotid endarterectomy patients who underwent in vivo morphologic evaluation of the carotid atheroma by high-resolution MRI, independent assessment of neurologic symptoms, measurement of hs-CRP levels, and histopathologic analysis of the plaque. Our main objective was to evaluate potential associations between the occurrence of intraplaque hemorrhage assessed by MRI and other clinical markers of carotid vulnerability. Methods  Patients The present study enrolled patients with definite carotid atherosclerotic disease and internationally accepted, guideline-based criteria for carotid endarterectomy.21, 22 Patients were selected between December 2004 and December 2005, at the Cardiovascular Surgery Division of the São Lucas Hospital of the Pontifical Catholic University of Rio Grande do Sul, Brazil. Patients with known infectious or autoimmune diseases, and those who were unable to undergo MRI or whose atherosclerotic plaque was considered to be unsuitable for histologic analysis (n = 2) were not included in the present study. Also excluded were patients with conditions might increase hs-CRP levels, including severe peripheral arterial disease, including pain at rest, ischemic cutaneous lesions, or gangrene, and those with acute coronary syndromes who had undergone surgical or percutaneous interventions ≤90 days. The present protocol was approved by the Ethics Committee of our institution, and all patients signed a written informed consent form before enrollment. Clinical characterization All patients were classified according to the presence and evolution of neurologic symptoms, as assessed by an experienced neurologist (M. F.) who was unaware of MRI data or other clinical variables. Patients were classified as (1) unstable (or recently symptomatic), defined as the presence of ipsilateral hemispheric symptoms in patients in whom plaques were removed ≤90 days of the event, or (2) stable (asymptomatic or remotely symptomatic), defined as patients with no ipsilateral neurologic symptoms or with ipsilateral hemispheric symptoms, but with endarterectomy performed >90 days after the event. Magnetic resonance imaging All MRI exams were performed on a Siemens Magneton Vision Plus apparatus (Siemens Inc, Erlangen, Germany). The MRI protocol included two different contrast-weighted images: time of flight (TOF) to estimate level of angiographic stenosis and T1-weighted (T1W) sequence to access intraplaque hemorrhage, using the same image window acquisition. Magnetic resonance angiography (MRA) was performed by the usual technique, in three-dimensional (3D) TOF pulse sequences, corresponding to the noncontrast phase, and gradient 3D Turboflash, related to the contrast phase (intravenous gadolinium). Luminal stenosis was determined according to North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria23 and evaluated by the ratio between the smallest diameter of the narrowed segment and the largest diameter of the internal carotid artery, distal to the lesion. The graduation of stenosis was adapted from Nederkoorn et al,24 divided into three categories: 50% to 69% stenosis, 70% to 90% stenosis, and stenosis >90%. The technique used to detect areas of hemorrhage was similar to the protocol described by Moody et al,17 with the purpose of identifying the presence of methemoglobin in the extracellular matrix. We used a 3D magnetization-prepared rapid gradient-echo pulse sequence, with 10.3 milliseconds of repetition time, 4 milliseconds of echo time, and 1000 milliseconds of delay time; flip angle, 15°; one acquisition. Fat suppression was used for T1W images to reduce signals from subcutaneous tissue. This combination produced signal amplification in T1W in areas containing recent thrombus or hemorrhage, identified by the hyperintense signal (carotid high signal). Whenever the brightness was more intense than in adjacent soft tissues, the signal was classified as positive for acute or recent hemorrhage. Images were obtained with a 30 × 30 cm2 field of view, matrix size, 256; and 1.07-mm slice thickness. MRIs were interpreted by two experienced blinded reviewers (J. R. H. and M. B. M.). The highest percentage of stenosis prevailed in the case of disagreement between the reviewers. Plaque length was measured and the proximal and distal margins were defined for comparisons with histology findings. Serum immunoinflammatory markers In the operating room, before anesthetic induction, 20 mL of blood was drawn from a peripheral vein and immediately processed. The level of hs-CRP was measured according to a nephelometric method by the Behring CardioPhase assay (Behring Inc, Marburg, Germany), in which monoclonal antibodies to human CRP were used in a cooled serum aliquot, as previously described.25 Surgical technique All patients were operated on by the same surgeon (L. C. A.) under general anesthesia, with orotracheal intubation and monitoring of mean arterial pressure. Dissection of the carotid bifurcation was performed according to the usual technique, avoiding hemostasis by compression to limit embolization or disarrangement of the plaque architecture. After infusion of intravenous heparin (1.0 mg/kg), an anterior longitudinal arteriotomy was performed, long enough to reach the margin of the normal artery wall, 1.0 cm cranially and caudally to the lesion. The atheroma was removed by detachment and immediately stored in a 10% formol solution. After removal of plaque debris, anticoagulation was reversed with intravenous protamine (1.0 mg/kg). Histologic analysis During surgery, every effort was made to avoid disruption of the plaque anatomy and to identify both the posterior-anterior and proximal-cranial references for subsequent comparison with MRI. Thus, before infusion of formol solution, the posterior and cranial surfaces of plaque specimens were dyed to define spatial markers for later comparisons to MRI findings, as recommended by Lovett et al.26 After decalcification and inclusion in paraffin block, 10-μm samples were sectioned at every 3.0 mm of the histologic block and stained with standard hematoxylin and eosin and Mallory trichromic. Analysis of histopathology was performed by an experienced pathologist (A. A. M.) who was unaware of clinical and laboratory data. Characterization of intraplaque hemorrhage was adapted from Lusby et al.27 Acute hemorrhage (<1 week) was defined by the presence of intact erythrocytes or as intracellular methemoglobin, identified as an orange-reddish coloring associated with focal macrophage activity. Recent hemorrhage (between 1 and 6 weeks) was characterized as the presence of lysed erythrocytes with extracellular methemoglobin or hemorrhage fragments dyed as a brownish red color, associated with agglomeration of macrophages with hemosiderin and giant cells. Late hemorrhage (>6 weeks) was classified according to the presence of amorphous material fragments, with hemosiderin dyed blue and bright pink with hematoxylin and eosin stain associated with calcification. The lack of these findings was characterized as an absence of hemorrhage. For statistical analysis, acute and recent bleeding was aggregated and defined as current intraplaque hemorrhage. Late or absent bleeding was also aggregated and defined as old or absent intraplaque hemorrhage. Fibrous cap was classified semi-quantitatively according to Hatsukami et al28 as normal whenever its thickness was ≥ 0.25 μm; or thin whenever its thickness was <0.25 μm at any point of analysis. Correlation between magnetic resonance findings and histology The protocol to match MRI images and histology sections has been described by Cappendijk et al.29 Slices 4-μm thick were cut every 3.0 mm from every plaque cross section, and the corresponding points on the angiographic MRI film were marked in coronal axis. MRI images were then reconstructed in axial axis, in the sequence for evaluation of the hyperintense signal and recorded on radiology films, with the same magnification window. Each MRI film was compared with the corresponding histologic cut, with the same spatial orientation in the anteroposterior and craniocaudal axes. Statistical analysis Continuous variables with normal distribution were expressed as average ± standard deviation and compared using the Student t test or analysis of variance (ANOVA). The hs-CRP results underwent logarithmic transformation because they did not present normal distribution and were also compared by using the Student t test or ANOVA, with post hoc analysis when appropriate. Categoric variables were expressed as frequencies and percentages. For comparisons between different groups, the χ2 test or the Fisher exact test were used. To assess the agreement between different methods of evaluation of the atherosclerotic plaque, we calculated the κ coefficient. A bicaudal P < 0.05 was considered statistically significant. Analyses were performed using SAS 8.0 software (SAS Institute, Cary, NC). Results Patient characteristics The study comprised 72 patients who underwent carotid endarterectomy. Two patients were excluded because their carotid plaques could not be adequately dissected during surgery due to fragmentation, impeding the subsequent alignment with MRI findings. Patients were predominantly male (66%) and hypertensive (89%) and had a mean age of 66 ± 9 years. As expected, several patients also reported a history of concomitant coronary arterial disease: 26% had symptoms of angina pectoris and 19% had sustained a previous myocardial infarction. A history (>90 days before the procedure) of a cerebral vascular attack (CVA) was found in 34% of patients and a transient ischemic attack in 16%. Statins were used by 69 patients (99%), and 46 (66%) also used the platelet-inhibiting drugs aspirin, ticlopidine, or clopidogrel. Other clinical characteristics and comorbidities are described in the Table. | | |  | Characteristic⁎ | All, N = 70 | Hyper-intense signal on MRI | P | |
|---|
| With, n = 45 | Without, n = 25 | |
|---|
| Age, y | 66 ±9.3 | 65±8.9 | 66±9.3 | .88 | | | Male, No. (%) | 46(66) | 31(69) | 15(60) | .45 | | | Active smoking, No. (%) | 19(27) | 10(22) | 9(36) | .46 | | | Hypertension, No. (%) | 62(89) | 42(93) | 20(80) | .09 | | | Diabetes, No. (%) | 32(46) | 20(44) | 12(48) | .77 | | | Obesity, No. (%) | 24(34) | 16(36) | 8(32) | .76 | | | Stable angina, No. (%) | 18(26) | 12(27) | 6(24) | .81 | | | Previous MI, No. (%) | 13(19) | 8(18) | 5(20) | .82 | | | Previous CABG, No. (%) | 14(20) | 10(22) | 4(16) | .53 | | | PAD, No. (%) | 33(47) | 23(51) | 10(40) | .37 | | | Arial fibrillation, No. (%) | 3(4) | 3(7) | 0 | .19 | | | Blood pressure, mm Hg | | | | | | | Systolic | 133±20 | 134±19 | 133±27 | .85 | | | Diastolic | 79±12 | 79±12 | 80±11 | .81 | | | Cholesterol, mg/dL | | | | | | | Total | 174±50 | 171±56 | 179±38 | .55 | | | LDL | 103±47 | 100±52 | 109±37 | .47 | | | HDL | 42±18 | 44±22 | 38±7 | .08 | | | Triglycerides, mg/dL | 185±11 | 193±117 | 172±109 | .47 | | | | |
| ⁎ Continuous data are presented as mean ± SD. |
According to the independent neurologic evaluation, 28 patients (40%) were considered stable, of whom 19 (27%) were asymptomatic, and 9 (13%) had experienced symptoms of ipsilateral ischemic stroke >90 days before carotid endarterectomy; whereas 42 (60%) were considered unstable (12 recent ipsilateral strokes and 30 TIAs). The average time between the occurrence of symptoms and collection of the atheroma in the clinically unstable group was 22 ± 11 days (range, 4 to 45 days). Most patients (79%) reported symptoms ≤30 days before surgery. Magnetic resonance findings MRA with gadolinium identified 15 patients (21.5%) with stenosis of 50% to 69%, 15 (21.5%) with 70% to 90% stenosis, and 40 (57%) with >90% stenosis. In the asymptomatic patients, 14 (16%) had luminal stenosis ≥70%, and only five (7%) were classified by MRA as having a 50% to 59% carotid stenosis. In the T1W sequence, a hyperintense signal suggesting intraplaque hemorrhage was identified in 45 patients (64%). Age, gender, traditional cardiovascular risk factors, and history of previous myocardial infarction or peripheral arterial disease were similar in patients with or without signs of intraplaque bleeding on MRI (Table). Of interest was that all patients who had a TIA >90 days before the surgery showed the hyperintense signal (P = .007), which was found in 17 of 24 patients who sustained a previous stroke. We also observed a significant association between neurologic symptoms and MRI findings: 98% of the unstable cases had a positive hyperintense signal on MRI, but only 14% of the stable patients showed the same finding (P < .001, Fig 1). There was an excellent agreement between the assessments of both radiologists. There was concordance in the assessment of the hyperintense MRI signal in all cases, whereas the κ coefficient was 0.95 in the evaluation of angiographic stenosis. Histopathologic findings and correlation with magnetic resonance imaging Fibrous cap thickness was >0.25 μm in 46 patients (66%) and <0.25 μm in 24 (34%). Intraplaque hemorrhage was described in the histologic analysis as acute in 26 patients (37%), recent in 19 (27%), old in 2 (3%), and absent in 23 (33%). There was excellent agreement between the histologic finding of acute or recent hemorrhage and the MRI findings (κ coefficient, 0.91; 95% confidence interval, 0.81 to 1.00). Only one of the 45 patients (2%) with a hyperintense MRI signal did not have acute or recent hemorrhage in the histologic analysis; conversely, only two of the 25 patients (8%) without a hyperintense MRI signal had acute or recent hemorrhage on pathology. Sensitivity and specificity of a positive MRI to detect intraplaque hemorrhage was 96%. However, no significant association between the presence of a positive hyperintense signal on MRI and fibrous cap thickness (P = .38) or carotid luminal stenosis (P = .92, Fig 2) was found. Fig 3 and Fig 4 depict examples of correlations between MRI and histologic data. As expected, excellent concordance between neurologic symptoms and histopathologic findings was also observed (χ2 p < .0001). Acute or recent hemorrhage in the histologic analysis was identified in 18% of the stable group (5 of 28) and in 98% of unstable patients (41of 42). C-reactive protein Mean hs-CRP values were 1.2 ± 1.5 mg/L in the 70 cases studied. The hs-CRP levels were essentially identical for the different degrees of carotid stenosis assessed by MRA (Fig 5, A), but they were significant higher in clinically unstable patients compared with neurologically stable patients (1.54 ± 1.7 vs 0.67 ± 0.8 mg/L, respectively; P = .006). Similarly, those patients who showed a positive hyperintense MRI signal also had higher hs-CRP levels (1.47 ± 1.7 vs 0.7 ± 0.8 mg/L; P = .01). In an aggregated analysis considering clinical characteristics and MRI findings, a progressive increase of hs-CRP levels was observed (P = .02, Fig 5, B). Levels of hs-CRP doubled in patients with a hyperintense MRI signal. Using the highest quartile of this marker (hs-CRP ≥1.58 mg/L) as the cutoff level, we observed a specificity of 96% and a sensitivity of 37% for the presence of intraplaque hemorrhage on histology. Discussion Carotid bifurcation atheroma causes 20% to 30% of CVAs and it is well established that the degree of angiographic stenosis is the major determinant of surgical intervention. However, a growing body of evidence clearly demonstrates that carotid plaque vulnerability is not directly influenced by the obstructive nature of the plaque but is mainly associated with specific structural, molecular, and biochemical disarrangements of the atheroma,6, 8, 30, 31 particularly involving local and systemic immunoinflammatory processes. Our data indicate that noninvasive assessment of carotid atherosclerotic plaques by high-resolution MRI can adequately identify important morphologic and structural aspects of the atheroma, in particular the presence of intraplaque hemorrhage. Furthermore, we showed that this finding is associated with increases in hs-CRP levels and instability of neurologic symptoms. Previous studies have assessed the association of hs-CRP levels and the presence of cerebral vascular disease. Data from the Framingham study indicate that men in the highest quartile of hs-CRP doubled their risk of ischemic stroke and transient ischemic attacks, whereas women tripled their risk.14 Wang et al32, 33 demonstrated that the development of plaques in the internal carotid artery, regardless of the presence of clinical disease, was more evident in the highest quartile of hs-CRP.33 In addition, the association of hs-CRP, carotid intimal-medial thickness, and CVA risk was prospectively assessed in 5417 elderly patients in the Cardiovascular Health Study.34 A strong positive correlation between hs-CRP levels and CVA risk was found in the highest tertile of thickening. In the present study, we evaluated hs-CRP levels in patients undergoing carotid endarterectomy. We used predefined criteria of clinical instability. Our results suggest a direct relationship between hs-CRP and clinical instability and demonstrate for the first time, to the best of our knowledge, a significant association between hs-CRP levels and MRI characteristics of vulnerability. Our data corroborate results of Garcia et al,15 who investigated the association between hs-CRP levels and histologic and immunocytologic aspects of carotid plaques. The levels of Hs-CRP were significantly higher in those cases classified as histologically unstable, demonstrating a positive correlation with macrophage infiltration and T lymphocytes in the plaque.15 In this scenario, our findings contribute to the understanding of the complex interplay of events that take place when a carotid plaque becomes unstable, potentially leading to the development of acute neurologic symptoms. It is reasonable to speculate that among several other factors, the physiopathologic basis for these processes involves both intraplaque hemorrhage and inflammatory responses. We demonstrate here that these processes are interconnected and may identify patients at greater risk of neurologic events. Recent investigations have attempted to identify in vivo morphologic characteristics of the vulnerable carotid atheroma. Several studies correlating different imaging techniques and histologic analyses were used to validate these techniques. The methodologic quality of these investigations was recently questioned in a systematic review of 73 studies in which only 23% adequately assessed the reproducibility of image acquisition and in which the histologic methods were comparable for only 12%. Lovett et al26 suggest strict recommendations in the preparation of histologic sections, such as the use of representative samples with a similar number of symptomatic and asymptomatic cases, detailed registration of the temporal relationship with symptoms, image acquisition without significant delay in relation to histologic analysis, careful spatial orientation of blocks, maximum 3-mm cuts, and blinded reading of both results.26 We attempted to comply with most of these strict quality criteria in the study design, although patient enrollment was not perfectly balanced between symptomatic and asymptomatic subjects. Nonetheless, our study demonstrated an excellent agreement between the presence of a hyperintense signal on high-resolution MRI and acute or recent intraplaque hemorrhage. Moody et al17 found a similar prevalence of carotid intraplaque bleeding by high-resolution MRI in symptomatic patients but observed a lower histologic concordance. Other recent studies have analyzed clinical instability and plaque morphology. Saam et al35 evaluated 23 patients by 1.5-T time-of-flight MRS, 1.5-T T1W, and T2W MRI and demonstrated a significant correlation between symptomatic plaques and several features of fibrous cap structure and intraplaque hemorrhage compared with contralateral asymptomatic plaques in the same patients. Takaya et al36 reported the evolution of 154 consecutive subjects, demonstrating that arteries with thinned or ruptured fibrous caps and intraplaque hemorrhage by MRI were associated with the occurrence of subsequent cerebrovascular events, suggesting the need for larger, multicenter studies to characterize the clinical role of plaque features for the prediction of subsequent ischemic events. Our results are also in agreement with a recent study by Chu et al19 that added the weighted sequence in T2 to distinguish fresh, recent, or old hemorrhage. These authors observed a moderate to strong agreement between MRI and histologic findings (κ coefficient, 0.7). Although we were unable to perform a detailed structural analysis of the fibrous cap by MRI, the presence of a hyperintense signal was not associated with a semi-quantitative evaluation of fibrous cap histology. This finding may indicate that other mechanisms not solely related to fibrous cap structure may be involved in the development of neurologic events. In this scenario, it is plausible to speculate that inflammatory processes mediated or identified by hs-CRP may be involved. The absence of a correlation between a high MRI signal and luminal stenosis evaluated by MRA concurs with current evidence indicating that the phenomena of positive remodeling and eccentricity are dominant in relation to the occlusive character of the atheroma in the genesis of ischemic ipsilateral strokes. Novel markers of carotid atherosclerotic instability capable of identifying inflammatory or prothrombotic activity inside the plaque, as shown in our study, have been recently suggested.16 High-resolution MRI has emerged as the imaging technique with the best technical profile to accurately recognize such findings.37 Some limitations related to our study design and analyses must be considered. The assessment of other serum markers, such as the CD40 ligand complex or leukocyte myeloperoxidase activity, could potentially add important information concerning local and systemic inflammatory activity. Hs-CRP, however, is the inflammatory marker that has been most widely evaluated in clinical and pathologic studies from both coronary and carotid arteries. We cannot ensure that a perfect alignment (particularly in the submillimeter range) was obtained between the histologic analysis and MRI imaging. This potential bias, however, does not invalidate the overall excellent agreement observed between MRI findings and intraplaque hemorrhage. The T1W sequence used in the current MRI protocol did not allow specific evaluation of fibrous cap structure. Also, the semi-quantitative analysis of fibrous cap thickness by histology, as proposed by Hatsukami et al,28 may have limited our assessment of the importance of fibrous cap structure. Finally, our statistical power was not adequate to allow stratified data analysis, particularly concerning histologic risk features. Conclusion Our results demonstrate that the presence of a hyperintense signal on high-resolution MRI of carotid arteries in patients undergoing carotid endarterectomy is associated with increased systemic inflammatory activity. This particular finding was not related to the degree of angiographic stenosis or to fibrous cap thickness. These results, when viewed in light of evidence from other related investigations, are consistent with the concept that luminal stenosis in extracranial atherosclerotic disease, as in coronary vascular processes, is not an adequate marker of atheroma vulnerability. Contemporary scientific evidences suggest that other structural, molecular, and biochemical characteristics that participate in the atherosclerotic process deserve to be prospectively assessed in future studies as potential predictors for a timely indication of carotid endarterectomy. Author contributions Conception and design: LC, LB, AM, HS, MF, JF, MB, LR Analysis and interpretation: LC, LB, AM, HS, MF, JF, MB, LR Data collection: LC, LB, AM, HS, MF, JF, MB, LR Writing the article: LC, LB, LR Critical revision of the article: LC, AM, HS, MF, JF, MB, LR Final approval of the article: LC, LB, AM, HS, MF, JF, MB, LR Statistical analysis: LC, LR Obtained funding: LC, LR Overall responsibility: LC, LB, LR References 1. 1Hankey GJ. Stroke: how large a public health problem, and how can the neurologist help?. Arch Neurol. 1999;56:748–754. MEDLINE |
CrossRef
2. 2Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB, Hademenos G, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke. 2001;32:280–299. 3. 3Guidelines for carotid endarterectomy (A multidisciplinary consensus statement from the Ad Hoc Committee of the American Heart Association). Circulation. 1995;91:566–579. MEDLINE 4. 4Fuster V, Moreno PM, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque. J Am Coll Cardiol. 2005;46:937–954. Abstract | Full Text |
Full-Text PDF (1527 KB)
|
CrossRef
5. 5Mann JM, Davies MJ. Vulnerable plaque: relation of characteristics to degree of stenosis in human coronary arteries. Circulation. 1996;94:928–931. MEDLINE 6. 6Rohde LE, Lee RT. Pathophysiology of atherosclerotic plaque development and rupture: an overview. Semin Vasc Med. 2003;3:347–354. MEDLINE |
CrossRef
7. 7Modifi R, Crotty TB, McCarthy P, Sheehan SJ, Mehigan D, Keaveny TV. Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease. Br J Surg. 2001;88:945–950. MEDLINE |
CrossRef
8. 8Mullenix OS, Andersen CA, Starnes BW. Atherosclerosis as inflammation. Ann Vasc Surg. 2005;19:130–138. Abstract | Full Text |
Full-Text PDF (918 KB)
|
CrossRef
9. 9Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice (A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association). Circulation. 2003;107:499–511.
CrossRef
10. 10Koenig W. Predicting risk and treatment benefit in atherosclerosis: the role of C-reactive protein. Int J Cardiol. 2005;98:199–206. Abstract | Full Text |
Full-Text PDF (151 KB)
|
CrossRef
11. 11Biasucci LM. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: clinical use of inflammatory markers in patients with cardiovascular diseases: a background paper. Circulation. 2004;110:e560–e567.
CrossRef
12. 12Makita S, Nakamura M, Hiramori K. The association of C-reactive protein levels with carotid intima-media complex thickness and plaque formation in the general population. Stroke. 2005;36:2138–2142.
CrossRef
13. 13Schillinger M, Exner M, Mlekusch W, Sabeti S, Amighi J, Nikowitsch R, et al. Inflammation and Carotid Artery--Risk for Atherosclerosis Study (ICARAS). Circulation. 2005;111:2203–2209.
CrossRef
14. 14Rost NS, Wolf PA, Kase CS, Kelly-Haes M, Silbershatz H, Massaro JM, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. 2001;32:2575–2579.
CrossRef
15. 15Garcia BA, Ruiz C, Chacon P, Sabin JÁ, Matas M. High-sensitivity C-reactive protein in high-grade carotid stenosis: risk marker for unstable carotid plaque. J Vasc Surg. 2003;38:1018–1024. Abstract | Full Text |
Full-Text PDF (106 KB)
|
CrossRef
16. 16Nighoghossian N, Derex L, Douek P. The vulnerable carotid artery plaque (Current imaging methods and new perspectives). Stroke. 2005;36:2764–2772.
CrossRef
17. 17Moody AR, Murphy RE, Morgan PS, Martel AL, Delay GS, Allder S, et al. Characterization of complicated carotid plaque with magnetic resonance direct thrombus imaging in patients with cerebral ischemia. Circulation. 2003;107:3047–3052.
CrossRef
18. 18Murphy RE, Moody AR, Morgan PS, Martel AL, Delay GS, Allder S, et al. Prevalence of complicated carotid atheroma as detected by magnetic resonance direct thrombus imaging in patients with suspected carotid artery stenosis and previous acute cerebral ischemia. Circulation. 2003;107:3053–3058.
CrossRef
19. 19Chu B, Kampschulte A, Ferguson M, Kerwin WS, Yarnykh VL, O’Brian KD, et al. Hemorrhage in the atherosclerotic carotid plaque: a high-resolution study. Stroke. 2004;35:1079–1084.
CrossRef
20. 20Kampschulte A, Ferguson MS, Kerwin WS, Nayak L, Polissar , Chu B, et al. Differentiation of intraplaque versus juxtaluminal hemorrhage/thrombus in advanced human carotid atherosclerotic lesions by in vivo magnetic resonance imaging. Circulation. 2004;110:3239–3244.
CrossRef
21. 21Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al.North American Symptomatic Carotid Endarterectomy Trial Collaborators Benefit of carotid endarterectomy in patients with symptomatic moderated or severe stenosis. N Engl J Med. 1998;339:1415–1425. MEDLINE |
CrossRef
22. 22MRC asymptomatic carotid surgery trial (ACST) collaborative group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomized controlled trial. Lancet. 2004;363:1491–1502. Abstract | Full Text |
Full-Text PDF (163 KB)
|
CrossRef
23. 23North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy im symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–453. MEDLINE 24. 24Nederkoorn PJ, van der Graaf Y, Hunink MG. Duplex ultrasound and magnetic resonance angiography compared with digital subtraction angiography in carotid artery stenosis: a systematic review. Stroke. 2003;34:1324–1332.
CrossRef
25. 25Whicher JT, Ritchie RF, Johnson AM, Baudner S, Bienvenu J, Blirup-Jensen S, et al. New international reference preparation for proteins in human serum (RPPHS). Clin Chem. 1994;40:934–938. MEDLINE 26. 26Lovett JK, Redgrave JNE, Rothwell PM. A critical appraisal of the performance, reporting, and interpretation of studies comparing carotid plaque imaging with histology. Stroke. 2005;36:1091–1097. 27. 27Lusby RJ, Ferrell LD, Ehrenfeld WK, Stoney RJ, Wylie EJ. Carotid plaque hemorrhage (Its role in production of cerebral ischemia). Arch Surg. 1982;117:1479–1488. MEDLINE 28. 28Hatsukami TS, Ross R, Polissar NL, Yuan C. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging. Circulation. 2000;102:959–964. 29. 29Cappendijk VC, Cleutjens KB, Kessels AG, Heeneman S, Schurink GW, Welten RJ, et al. Assessment of human atherosclerotic carotid plaque components with multisequence MR imaging: initial experience. Radiology. 2005;234:487–492. MEDLINE |
CrossRef
30. 30Jander S, Sitzer M, Schumann R, Schroeter M, Siebler M, Steinmetz H, et al. Inflammation in high-grade carotid stenosis (A possible role for macrophages and T cells in plaque destabilization). Stroke. 1998;29:1625–1630. MEDLINE 31. 31Gonçalves I, Moses J, Dias N, Pedro LM, Fernandes JF, Nilsson J, et al. Changes related to age and cerebral vascular symptoms in the extracellular matrix of human carotid plaques. Stroke. 2003;34:616–622.
CrossRef
32. 32Wang TJ, Nam B, Wilson PF, Wolf PA, Levy D, Polak JF, et al. Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham heart study. Arterioscler Thromb Vasc Biol. 2002;22:1662–1667.
CrossRef
33. 33Wang TJ, Nam B, Wilson PWF, Wolf PA, Levy D, Polak JF, et al. Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham heart study. Arterioscler Thromb Vasc Biol. 2002;22:1662–1667.
CrossRef
34. 34Cao JJ, Thach C, Manolio TA, Psaty BM, Kuller LH, Chaves PH, et al. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation. 2003;108:e9002–e9003. 35. 35Saam T, Cai J, Ma L, Cai YO, Fergusom MS, Polissar NL, et al Comparison of symptomatic and asymptomatic atherosclerotic carotid plaque features with in vivo MR imaging. Radiology. 2006;240:464–472. MEDLINE |
CrossRef
36. 36Takaya N, Yuan C, Chu B, Saam T, Underhill H, Cai J, et al. Association between carotid plaque characteristics and subsequent ischemic cerebrovascular events (A prospective assessment with mri—initial results). Stroke. 2006;37:818–823.
CrossRef
37. 37Yuan C, Mitsumori LM, Beach KW, Maravilla KR. Carotid atherosclerotic plaque: noninvasive MR characterization of vulnerable lesions. Radiology. 2001;221:285–299. MEDLINE |
CrossRef
a Division of Adult Cardiovascular Surgery, Cardiovascular Sciences of the Federal University of Rio Grande do Sul, Puerto Alegre, Brazil b Division of Pathology, Cardiovascular Sciences of the Federal University of Rio Grande do Sul, Puerto Alegre, Brazil c Division of Rheumatology, Cardiovascular Sciences of the Federal University of Rio Grande do Sul, Puerto Alegre, Brazil d Division of Neurology, Cardiovascular Sciences of the Federal University of Rio Grande do Sul, Puerto Alegre, Brazil e Center for Diagnostic Imaging of the Pontifical Catholic University of Rio Grande do Sul’s São Lucas Hospital, Puerto Alegre, Brazil f Cardiology Division of the Hospital de Clínicas de Porto Alegre, Puerto Alegre, Brazil.  Correspondence: Luis E. Rohde, MD, Post-graduate Program in Cardiology and Cardiovascular Sciences of the Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, Rm 2060, Second Floor, Porto Alegre 90035 903 Brazil.
Competition of interest: none. PII: S0741-5214(07)01252-9 doi:10.1016/j.jvs.2007.07.041 © 2007 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. | |
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