Critical carotid stenoses: morphologic and chemical similarity between symptomatic and asymptomatic plaques

To identify microanatomic and chemical features that may mark the transition from asymptomatic to symptomatic atherosclerotic carotid lesions, we evaluated 62 carotid artery bifurcation plaques including 45 high-grade stenoses removed at endarterectomy and 17 nonstenotic plaques recovered at autopsy. Morphologic features were evaluated on multiple-interval histologic sections and were graded for the presence of hemorrhage, ulceration, thrombosis, lumen surface irregularity, and calcification. Plaque hemorrhage, recent and remote, was found in most of the specimens, and did not discriminate between symptomatic and asymptomatic stenotic plaques. High-grade carotid stenotic plaques were associated with a significantly higher incidence of ulceration (53%), thrombosis (49%), and lumen irregularity (78%) when compared to nonstenotic asymptomatic plaques (6%, 0%, and 17%, respectively; p less than 0.01). Although these features were more prominent in lesions that produced symptoms, they were present in 80% of the stenotic bifurcations, and did not distinguish between symptomatic and asymptomatic endarterectomy plaques. No significant differences were found between symptomatic and asymptomatic high-grade lesions with respect to collagen, DNA, total cholesterol, fibrinogen, lipase, elastase, or collagenase content. We conclude that intraplaque hemorrhage is commonly seen in carotid plaques even without severe stenosis, and it does not appear to be a dominant determinant of symptoms. Ulceration and surface thrombi that may lead to cerebral embolization are prominent features in markedly stenotic plaques even when symptoms are absent. The disruptive processes that underlie plaque instability appear to be closely associated with plaque size and stenosis rather than plaque composition.     

Pixel distribution analysis of B-mode ultrasound scan images predicts histologic features of atherosclerotic carotid plaques

BACKGROUND: The correlation of B-mode ultrasonographic morphology with histologic characteristics of atherosclerotic carotid plaques remains ill-defined. The classification of plaques with recently reported measures of plaque echogenicity and heterogeneity has been unsatisfactory. We used computer-assisted duplex ultrasound (DU) scan image analysis to determine echogenicity of specific tissues in control subjects. This information was used to quantify each tissue in imaged carotid plaques with pixel distribution analysis (PDA). These objective observations then were quantitatively compared with plaque histology in symptomatic and asymptomatic patients. METHODS: We performed standardized DU scanning of healthy tissues in 10 volunteer subjects and of 20 carotid artery plaques (7 symptomatic and 13 asymptomatic) in 19 patients with carotid stenosis. The plaques underwent histologic analysis after carotid endarterectomy. The grayscale intensity ranges of blood, lipid, fibromuscular tissue, and calcium were calculated in the control subjects. With computer-assisted image analysis, B-mode images of plaques were linearly scaled to normalize data. Pixel distribution within the images then was analyzed. The grayscale ranges of known tissues obtained from control subjects helped define the amount of intraplaque hemorrhage, lipid, fibromuscular tissue, and calcium within carotid plaque images. This analysis was correlated with tissue composition measurements on histologic sections of excised plaques. RESULTS: The median grayscale intensity (range) in control subjects was 2 (0 to 4) for blood, 12 (8 to 26) for lipid, 53 (41 to 76) for muscle, 172 (112 to 196) for fibrous tissue, and 221 (211 to 255) for calcium. PDA-derived predictions for blood, lipid, fibromuscular tissue, and calcium within carotid plaques correlated significantly with the histologic estimates of each tissue respectively (blood: P =.012; lipid: P =.0006; fibromuscular: P =.035; and calcium: P =.0001). A significantly higher amount of blood and lipid was seen within symptomatic plaques compared with asymptomatic ones (P =.0048 and P =.026, respectively). Conversely, a larger amount of calcification was noted within asymptomatic plaques (P =.0002). CONCLUSION: Computer-assisted PDA of DU scan images accurately quantified intraplaque hemorrhage, fibromuscular tissue, calcium, and lipid. Symptomatic plaques had lower calcium content but larger amounts of intraplaque hemorrhage and lipid. Quantitative PDA may be used to determine carotid plaque tissue composition to assist in the identification of symptomatic and potentially unstable asymptomatic plaques.     

Differences in the detection of cyclo-oxygenase 1 and 2 proteins in symptomatic and asymptomatic carotid plaques.

BACKGROUND: The expression of cyclo-oxygenase (COX) 1 and 2 has been demonstrated in atherosclerotic arteries. In the present study this was correlated with symptoms arising from a carotid plaque. METHODS: Carotid plaques from 12 asymptomatic patients were compared with 11 plaques from patients who had had neurological symptoms within the preceding 30 days. Sections were stained with haematoxylin and eosin, elastin van Gieson and goat antihuman antibodies to COX-1 and COX-2. Plaque morphology was correlated with neurological symptoms. The area with positive COX-1 and COX-2 staining was measured by computerized planimetry in entire cross-sections and in specific areas of the plaque. RESULTS: There was a significant association between cap thinning and plaque rupture with symptoms (P = 0.003). The percentage area of positive staining in entire cross-sections for both COX-1 and COX-2 was significantly greater in symptomatic plaques (P = 0.001 and 0.0004 respectively). Staining in symptomatic plaques was significantly greater in the cap (COX-1: P = 0.001; COX-2: P = 0.0001) and shoulder (COX-1: P = 0.008; COX-2: P = 0.007) regions of the plaque. COX-1 expression in the sclerotic area was not increased (P = 0.15) although COX-2 staining was significantly greater (P = 0.04). CONCLUSION: Both COX-1 and COX-2 detection was increased in symptomatic plaques. COX may contribute to plaque rupture and the onset of symptoms.     

B-mode ultrasonographic investigations of morphological changes in endarterectomized carotid artery

BACKGROUND: The aim of this study was to assess morphological changes in the endarterectomized carotid region using B-mode ultrasonography (USG). METHODS: USG examinations were performed on 54 Japanese patients who underwent carotid endarterectomy (CEA). The endarterectomized regions were periodically investigated and the intima-media thickness (IMT) was measured. RESULTS: Postoperative USGs revealed an evident step formation (type I: 20.4%), a gentle slope (type II: 42.6%), or complete smoothness (type III: 37.0%) at the junction of the endarterectomized carotid region and the common carotid artery (CCA). The IMT of the CCA progressively increased from type I to type III. Patients were followed up for an average of 2.7 years. The new intima-media complex (IMC) was confirmed in all cases after 9 months; it was visualized as an isoechoic layer (7%) or a mixture of iso- and hypoechoic layers (93%). Changes in the IMT during the follow-up period were classified into three groups: no change (group I: 23.1%), decrease (group II: 15.4%), and increase (group III: 61.5%). CONCLUSIONS: USG is useful to clarify the complicated healing processes of the endarterectomized carotid artery.     

Chlamydia pneumoniae DNA in patients with symptomatic carotid atherosclerotic disease

OBJECTIVE: We evaluated the correlation between the presence of Chlamydia pneumoniae in atherosclerotic carotid plaques, lymph nodes, and peripheral blood mononuclear cells (PBMCs), and symptomatic carotid atherosclerotic disease. METHODS: Fifty-one consecutive patients undergoing carotid endarterectomy were enrolled; 18 of the 51 patients had symptomatic disease, whereas 33 had asymptomatic disease. Detection of C pneumoniae DNA in atherosclerotic carotid plaques, lymph nodes, and PBMCs was performed with polymerase chain reaction (PCR). C pneumoniae antibodies were measured with a microimmunofluorescence test. RESULTS: C pneumoniae DNA in atherosclerotic carotid plaques was detected in 44.4% of patients with symptomatic disease and in 30.3% of those with asymptomatic disease (P =.48). C pneumoniae DNA in lymph nodes was detected in 33.3% of patients with symptomatic disease and 18.2% of those with asymptomatic disease (P =.19). Prevalence of C pneumoniae DNA in PBMCs was significantly higher in patients with symptomatic disease (72.2%) compared with those with asymptomatic disease (30.3%) (P =.01). Serologic results support the association between C pneumoniae DNA in PBMCs and symptomatic carotid atherosclerotic disease, because seropositivity for anti-chlamydial immunoglobulin (Ig) A antibodies was significantly higher in PCR-positive PBMCs in patients with symptomatic disease compared with patients with asymptomatic disease (P =.02). CONCLUSIONS: Detection of C pneumoniae in PBMCs shows that C pneumoniae may be associated with symptomatic carotid atherosclerotic disease. Although we believe there is need for standardization of PCR methods and for assessing sensitivity, specificity, and predictive values of the tests, we suggest that presence of C pneumoniae DNA in PBMCs is a valid surrogate marker of risk for endovascular chlamydial infection. Only long-term cohort studies and interventional trials will clarify the etiopathogenic role of C pneumoniae.     

Metalloproteinase levels are decreased in symptomatic carotid plaques

BACKGROUND: Matrix metalloproteinase enzymes (MMP) have been identified in carotid atherosclerotic plaques, but their role in the development of clinical symptoms remains ill defined. We correlated the activity and levels of metalloproteinase enzymes and their inhibitors in human carotid plaques to ischemic neurologic events. METHODS: Carotid plaques were collected at the time of endarterectomy from 23 patients with carotid stenosis. Sixteen patients were asymptomatic and 7 patients had symptoms of stroke or transient ischemic attack within 6 weeks of surgery. Protein was extracted from the plaques, proteolytic activity was determined by gelatin zymography, and pro-MMP and tissue inhibitor of metalloproteinase (TIMP) enzyme content were measured by ELISA assay. Macrophage accumulation in the plaque was determined using immunohistochemistry. RESULTS: Plaques from symptomatic patients had decreased proteolytic activity on substrate gel zymography at the 62- and 92-kDa regions (corresponding to active MMP-2 and pro-MMP-9). A decrease in pro-MMP-9 (8.21 +/- 2.35 vs 17.42 +/- 3.14 ng, P < 0. 05) and an increase in TIMP-2 protein (12.62 +/- 0.58 vs 10.56 +/- 0. 77 ng, P < 0.05) were noted on ELISA in plaques from symptomatic patients. No difference was noted in macrophage accumulation in the plaques between the two groups. CONCLUSIONS: Plaques from patients who present with ischemic neurologic symptoms have decreased proteolytic activity associated with decreased pro-MMP-9 and increased TIMP-2 protein levels. These data suggest that metalloproteinase enzymes are not responsible for plaque instability in the carotid circulation and may in fact promote plaque stability.     

Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients

INTRODUCTION: Atherosclerotic carotid artery disease is responsible for a variety of clinical presentations, ranging from asymptomatic to cerebral ischemic events. Considering the upcoming use of noninvasive imaging modalities, plaque characteristics could serve as a marker in the selection of patients eligible for carotid endarterectomy (CEA). This would be more likely if characteristics corresponded with clinical manifestations and were predictive of future events. In this study, we hypothesized that plaque characteristics correlate with the clinical presentation of carotid artery disease. METHODS: We included 404 patients undergoing a carotid endarterectomy (CEA). Ipsilateral clinical symptoms and duplex measurements were recorded. Patients could be asymptomatic (23.5%) or symptomatic with stroke (26.5%), transient ischemic attack (TIA) (36.1%), or amaurosis fugax (AFX) (13.9%). Plaques were stained and semi-quantitatively analyzed for the presence of macrophages, smooth muscle cells, collagen, calcifications, and thrombus. Plaques were categorized in three phenotypes by their overall presentation and the amount of fat. In addition, plaque matrix metalloproteinase (MMP) activity and cytokines expressions were measured. RESULTS: Fibrous, fibro-atheromatous, and atheromatous plaques were observed in 30.2%, 35.6%, and 34.2%, respectively. Atheromatous plaques were more prevalent in patients with stroke and TIA compared with asymptomatic patients or patients with AFX (P = .001). Collagen staining was less evident in patients with TIA and stroke compared with asymptomatic patients or patients with AFX (P < .001). Plaques of patients with TIA and stroke showed significantly higher activity levels of MMP-8 and MMP-9 and higher levels of interleukin-8 compared with asymptomatic and AFX patients. CONCLUSION: Plaque phenotype of patients with TIA is comparable to that of patients with stroke; whereas, the plaque phenotype of patients with AFX resembles the plaque phenotype of asymptomatic patients. Follow-up studies should be encouraged to determine whether plaque characteristics visualized by imaging techniques might help to identify patients most likely to benefit from CEA.     

Cerebral hemodynamics in symptomatic and asymptomatic patients with severe unilateral carotid stenosis before and after carotid endarterectomy.

BACKGROUND: Data concerning hemodynamic status prior to and after carotid endarterectomy (CEA) in symptomatic and asymptomatic patients is insufficient. Transcranial Doppler (TCD) provides information regarding compensatory collateral flow as well as mechanisms of cerebral autoregulation in patients with carotid stenosis. PATIENTS AND METHODS: Forty eight symptomatic and 81 asymptomatic patients with unilateral severe carotid stenosis were examined by TCD before and in early postoperative period after CEA. RESULTS: Cigarette smoking was the only risk factor significantly more frequent in symptomatic patients. Preoperative anterior cerebral artery (ACA) and middle cerebral artery (MCA) asymmetry, basilar artery velocity and number of ophthalmic arteries with reversed flow, were not significantly different between the two groups. Pulsatility index, cerebrovascular reactivity and flow acceleration on the side of stenosis were significantly lower in symptomatic patients. After surgery there was a significant improvement of all TCD parameters in symptomatic as well as asymptomatic patients. CONCLUSIONS: The exhausted ability of cerebral autoregulation is an important factor differentiating between symptomatic and asymptomatic patients with severe carotid stenosis. Successful surgery provides good recovery of cerebral hemodynamics in both symptomatic and asymptomatic patients.     

Optimal contemporary management of symptomatic and asymptomatic carotid artery stenosis

This commentary addresses the issue of optimal contemporary management of symptomatic and asymptomatic carotid artery stenosis. Based on current data, carotid endarterectomy (CEA) should be performed in the majority of patients with symptomatic carotid artery stenosis. Carotid artery stenting (CAS) should be reserved for a minority of these symptomatic patients, in whom CEA is contraindicated. In asymptomatic patients, all should be placed on best medical treatment (BMT). With the use of one or more of the proposed stroke risk stratification models or some as yet undetermined method, the identification of those asymptomatic individuals may be possible in whom stroke risk is higher than usual with BMT. This asymptomatic subgroup, which may be small and is yet to be determined with certainty, could be offered an invasive carotid procedure (either CAS or CEA).     

Indications for treatment of symptomatic atherosclerotic carotid artery disease

Although the incidence of stroke and stroke mortality have declined during the past few decades, stroke still ranks third as a cause of death and a primary cause of long-term disability in most industrialized societies. Atherosclerotic disease at the carotid bifurcation accounts for approximately 20% to 30% of all ischemic strokes. In this article, the indications for treatment of symptomatic internal carotid artery stenosis are reviewed.     

Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques in patients with asymptomatic carotid stenosis undergoing coronary artery bypass grafting: an ultrasmall superparamagnetic iron oxide enhanced magnetic resonance study.

INTRODUCTION: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of Magnetic Resonance (MR) defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles, within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis in a cohort of patients undergoing coronary artery bypass grafting (CABG). METHODS: 10 patients awaiting CABG with asymptomatic carotid disease and 10 completely asymptomatic individuals with no documented coronary artery disease underwent multi-sequence MR imaging before and 36 hours post USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant, normalised to adjacent muscle signal, was calculated following USPIO administration. RESULTS: The mean percentage of quadrants showing signal loss was 94% in the CABG group, compared to 24% in the completely asymptomatic individuals (p<0.001). The carotid plaques from the CABG patients showed a significant mean signal intensity decrease of 16.4% after USPIO infusion (95% CI 10.6% to 22.2%; p<0.001). The truly asymptomatic plaques showed a mean signal intensity increase (i.e. enhancement) after USPIO infusion of 8.4% (95% CI 2.6% to 14.2%; p=0.007). The mean signal difference between the two groups was 24.9% (95% CI 16.7% to 33.0%; p<0.001). CONCLUSIONS: These findings are consistent with the hypothesis that inflammatory atheroma is a systemic disease. The carotid territory is more likely to take up USPIO if another vascular territory is symptomatic.     

Natural history of asymptomatic ulcerative plaques of the carotid bifurcation

In 79 patients with 91 asymptomatic ulcerating lesions of the carotid bifurcation who were followed an average of 54 months, there were two strokes, one of which was preceded by a warning transient ischemic attack. These data suggest that asymptomatic type A and type B carotid ulcerating lesions do not carry a significant early risk of stroke and do not warrant prophylactic carotid endarterectomy. However, the effect of antiplatelet drugs and anticoagulation in enhancing the development of subintimal hemorrhagic lesions remains uncertain. Further data with serial follow-up, preferably by noninvasive means, will be necessary to define the evolution of asymptomatic ulcerating carotid plaques and eventually permit identification of those lesions that have significant stroke potential.     

A reassessment of carotid endarterectomy in the face of contralateral carotid occlusion: surgical results in symptomatic and asymptomatic patients

OBJECTIVE: Total occlusion of the contralateral internal carotid artery has often been considered to be a predictor of poor outcome after carotid endarterectomy (CEA) of ipsilateral carotid stenosis. Data from both the North American Symptomatic Carotid Endarterectomy Trial and the Asymptomatic Carotid Atherosclerosis Study have suggested this to be true. However, each of these trials had relatively few patients with contralateral occlusion in the surgical arms of the studies. Recently, advocates of carotid angioplasty and stenting have suggested that this technique may be preferable in patients with a contralateral occlusion because of the perceived poor outcome with surgery. The purpose of this study was to review a large series of CEAs performed in patients with contralateral occlusion to see whether results differed from patients with patent contralateral arteries and to determine whether the presence of preoperative symptoms was an important factor in outcome in these cases. PATIENTS AND METHODS: A review was conducted of a prospectively compiled database of all primary CEAs performed at our institution from 1985 to 1999. Surgery was performed on 2420 patients, of whom 338 (14.0%) had contralateral total occlusion. RESULTS: Patients with contralateral total occlusion were more likely to be symptomatic (65.7% versus 60.1%; P =.1), male (70.9% versus 58%; P <.001), and hypertensive (63.9% versus 58.4%; P =.07) with a positive smoking history (42.6% versus 31.4%; P <.001) than patients with patent contralateral carotid artery. No significant difference was seen in the rates of perioperative neurologic events between patients with contralateral occlusion (3.0%) and those without (2.1%; P =.34). Among the total of 913 asymptomatic patients, of whom 115 had contralateral occlusion, no difference was seen in the rate of perioperative neurologic events (1.8% for contralateral occlusion cases; 1.9% for cases without contralateral occlusion). Among the total of 1507 symptomatic patients, of whom 223 had contralateral occlusion, no significant difference was seen in the rate of perioperative neurologic events (3.7% for contralateral occlusion cases; 2.2% for cases without contralateral occlusion; P =.2). CONCLUSION: The presence of contralateral occlusion does not appear to increase the perioperative risk of CEA. Although the risk of CEA in symptomatic patients with contralateral occlusion may be slightly increased, this must be weighed against the risk with medical treatment alone. CEA can be performed safely in patients with contralateral occlusion, which should not necessarily be considered a high-risk condition for surgery in favor of angioplasty and stenting.