Carotid arterial intraplaque hemorrhage and calcification influences cerebral hemodynamics

We evaluated associations between cerebral blood flow (CBF) and histopathological features in atherosclerotic lesions of the internal carotid artery. Cerebrovascular reactivity (CVR) and CBF were measured in 72 patients with unilateral carotid artery stenosis who underwent Xe-CT before carotid endarterectomy. Collateral blood flow was estimated as stump pressure. Proportions of fibrous tissue, intraplaque hemorrhage (IPH), and calcification were pathologically compared with the entire plaque body. The Spearman’s rank test and stepwise multiple linear regression analysis revealed that the IPH rate significantly and negatively correlated with CBF, whereas the calcification rate positively correlated with CVR. One-way analysis of variance showed that IPH and the absence of calcification might confer a risk for CBF and CVR reduction. Thus, not only the stenosis rate but also the degree of IPH and calcification in carotid arterial plaque are notable risk factors for ischemic stroke.     

颈动脉粥样斑块的MRI诊断价值

目的：探讨颈动脉粥样斑块的MRI影像特点,以提高对颈动脉粥样斑块成分及性质的认识。方法回顾性分析2013年11月～2014年5月期间13例颈动脉粥样斑块的MRI病例资料,并与颈动脉内膜剥脱术的病理结果相对照,总结其影像信号特点。结果13个病例共18个粥样硬化斑块,颈动脉内膜剥脱术取出13个斑块;13例斑块存在脂质坏死池;6例纤维帽撕裂;7例斑块内出血;11例斑块内钙化;4例炎性细胞浸润。结论颈动脉粥样斑块的磁共振信号具有特征性,磁共振成像能有效评估斑块的稳定性。     

Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events

BACKGROUND: Carotid endarterectomy is beneficial in severe (>70%) symptomatic carotid stenosis. The risk of stroke in moderate carotid stenosis (50%-69%) is modest, and so the role of carotid endarterectomy in this group is unclear. Intraplaque hemorrhage is associated with advanced atherosclerosis and can be detected in the carotid arteries by magnetic resonance imaging. This study evaluates whether magnetic resonance imaging detected intraplaque hemorrhage (MR IPH) can identify patients with symptomatic mild to moderate carotid stenosis who are at higher risk of ipsilateral transient ischemic attack (TIA) and stroke. METHODS: Prospective longitudinal cohort study of symptomatic patients with mild to moderate (30%-69%) carotid stenosis followed up for 2 years after imaging for IPH using magnetic resonance imaging. RESULTS: Sixty four participants were followed up for a median of 28 months (interquartile range 26-30) after MRI of the carotid arteries. Thirty-nine (61%) ipsilateral arteries showed intraplaque hemorrhage. During follow-up, five ipsilateral strokes and a total of 14 ipsilateral ischemic events were observed. Thirteen of these ischemic events, of which five were strokes, occurred in those with ipsilateral carotid intraplaque hemorrhage (hazard ratio = 9.8, 95% confidence interval 1.3-75.1, P = .03). CONCLUSIONS: MR IPH is a good predictor of ipsilateral stroke and TIA in patients with symptomatic mild to moderate (30%-69%) carotid stenosis. This technique could help in the selection of patients for carotid endarterectomy.     

Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology.

PURPOSE: Symptomatic carotid disease resulting from generation of thromboemboli has been associated with plaque instability and intraplaque hemorrhage. These features of the lesion could be influenced by the fragility and position of neovessels within the plaque. The purpose of this study was to determine whether any association exists between neovessel density, position, morphology, and thromboembolic sequelae. METHODS: Carotid endarterectomy samples were collected from 15 asymptomatic patients with greater than 80% stenoses and from 13 highly symptomatic patients who had suffered ipsilateral carotid stenotic events within 1 month of surgery. Both groups were matched for gender, age, risk factors, degree of carotid artery stenosis, and plaque size. Samples were stained with hematoxylin/eosin and van Geison. Immunohistochemistry was performed by using an endothelial specific antibody to CD31. Plaques were assessed for histologic characteristics, and neovessels were counted and characterized by size, site, and shape. RESULTS: There were significantly more neovessels in plaques (P <.00001) and fibrous caps (P <.0001) in symptomatic compared with asymptomatic plaques. Neovessels in symptomatic plaques were larger (P <.004) and more irregular. There was a significant increase in plaque necrosis and rupture in symptomatic plaques. Plaque hemorrhage and rupture were associated with more neovessels within the plaque (P <.017, P <.001) and within the fibrous cap (P <.046, P <.004). Patients with preoperative and intraoperative embolization had significantly more plaque and fibrous cap neovessels (P <.025, P <.001). CONCLUSION: Symptomatic carotid disease is associated with increased neovascularization within the atherosclerotic plaque and fibrous cap. These vessels are larger and more irregular and may contribute to plaque instability and the onset of thromboembolic sequelae.     

Contribution of angiotensin-converting enzyme and angiotensin II to ischemic stroke: their role in the formation of stable and unstable carotid atherosclerotic plaques

BACKGROUND: The angiotensin-converting enzyme/angiotensin II (ACE/Ang II) system is a strong contributor to intimal hyperplasia in atherosclerotic lesions. To illuminate its role in ischemic stroke, we examined the expression of ACE/Ang II in stable and unstable carotid atherosclerotic plaques from symptomatic and asymptomatic patients. METHODS: Using immunohistochemical methods, we studied differences between carotid atherosclerotic lesions obtained at carotid endarterectomy (CEA) from symptomatic (n = 36) and asymptomatic (n = 28) patients. The specimens were classified as stable (n = 30) and unstable (n = 34) plaques, and their fibrous cap, lipid core, and shoulder lesion were examined. We used antibodies against smooth muscle cells (SMC), macrophages, endothelial cells (EC), ACE, and Ang II. RESULTS: Of 28 lesions from asymptomatic patients, 20 (71.4%) manifested features characteristic of stable plaques: the expression of ACE/Ang II co-localized with SMC, EC, and macrophages in the shoulder lesion. In contrast, 26 of 36 symptomatic lesions (72.2%) exhibited the typical features of unstable plaques: dense accumulations of macrophages near the luminal surface in the shoulder lesion and weak immunoreactivity for ACE/Ang II, EC, and SMC. Furthermore, most of the lesions were accompanied by early stage atherosclerotic lesions (satellite lesions) that were strongly immunoreactive with macrophages, EC, and ACE/Ang II. CONCLUSIONS: ACE/Ang II expression may induce the proliferation of SMC and EC and result in the formation of carotid atherosclerotic plaques with a thick fibrous cap. Notably, the shoulder lesion of unstable plaques exhibited a thin fibrous cap and faintly expressed ACE/Ang II. Lack of the ACE/Ang II system may contribute to the final step in plaque rupture.     

Diagnostic imaging of carotid stenosis: ultrasound, magnetic resonance imaging, and computed tomography angiography

Carotid artery stenosis is increasingly a cause of stroke in Japan. Diagnostic imaging techniques are available, including ultrasound, 3D computed tomography angiography (CTA), magnetic resonance imaging (MRI), and cerebral angiography (DSA). The stenosis ratio measuring vessel diameter is a major criteria for surgical indications. CTA and DSA are definitive diagnostic procedures. Plaque imaging reveals a lipid-rich core, intraplaque hemorrhage, and thin fibrous cap. Atheromatic plaque with these components of vulnerable plaque is also a risk factor for stroke in addition to the stenosis ratio. As screening methods, ultrasound and magnetic resonance angiography are useful. Ultrasound and MRI provide valuable information on plaque imaging. Angiography remains essential for carotid stenting. For screening study prior to surgical or endovascular treatment and follow-up, the appropriate imaging modality should be selected for each patient with carotid stenosis to prevent stroke.     

Comparison of Vascular Smooth Muscle Cell Apoptosis and Fibrous Cap Morphology in Symptomatic and Asymptomatic Carotid Artery Disease

The biological cascades that lead to carotid plaque disruptions and symptoms are largely unknown. Certain cellular events within the plaque might be responsible for destabilizing the plaque, though the popular belief is that the plaque size is directly related to symptoms. The aim of our study was to assess the morphology of the fibrous cap and apoptosis in the plaque and compare these two pathological features in symptomatic and asymptomatic carotid artery disease. Our work was carried out in plaques obtained following carotid endarterectomy performed for symptomatic disease (including hemispheric transient ischemic attacks, amaurosis fugax, or stroke) or asymptomatic high-grade severe stenosis. Scion images of Gomori's stained sections were used to measure fibrous cap thickness and area. TUNEL assay was performed to assess the extent of apoptosis. The results indicated that the area of the fibrous cap did not significantly correlate with the presence of symptoms. There was a higher percentage of apoptotic nuclei and the thinner fibrous cap in symptomatic plaques than in asymptomatic plaques. This finding suggests that these factors might be involved in destabilizing plaque, causing rupture and leading to symptomatic carotid disease.     

Identification of high-risk carotid artery stenosis: motion of intraplaque contents detected using B-mode ultrasonography

Object Identification of the risk of rupture and vulnerability of arterial plaque is not yet clearly understood. The aim of this study was to assess the clinical features of the motion of intraplaque contents (MIC) detected by B-mode ultrasonography. The MIC is characterized by the peculiar movement of the intraplaque contents that is not synchronized with the heartbeat; however, the movement of the carotid artery (CA) wall depends on the heartbeat. Methods From January 2008 to November 2010, 1798 consecutive patients with transient ischemic attacks (TIAs) or acute ischemic stroke underwent CA ultrasonography for the examination of the MIC. Patients with CA stenosis greater than 50% were followed up until they underwent carotid endarterectomy or CA angioplasty and stent placement. If neither of these procedures were used, the patients were followed up at 90 days. Chi-square and Mann-Whitney tests were performed to compare the categorical and continuous demographic data and risk factors. The effect of the MIC on the rate of recurrent cerebral ischemia was examined using Kaplan-Meier and univariate Cox regression analyses. Results One hundred and fifteen patients had CA stenosis greater than 50%. Among these 115 patients, 58 with a total of 59 CA stenoses had MIC. Twenty-four recurrent ischemic events were associated with MIC, whereas only 6 such events occurred in the absence of MIC. The MIC decreased event-free survival (log-rank test = 15.8, p < 0.001); univariate Cox analysis confirmed that MIC increased the risk of a recurrent ischemic event (HR 5.12, 95% CI 2.08-12.58; p < 0.001). Conclusions The MIC is one of the findings of vulnerable plaques. The MIC is more useful in predicting the recurrence of TIAs or ischemic events in patients with symptomatic CA stenosis.     

Imaging of the high-risk carotid plaque: magnetic resonance imaging

The emergence of the concept of high-risk atherosclerotic plaque has led to considerable interest in noninvasive imaging techniques to identify high-risk features before clinical sequelae. For plaques in the carotid arteries, magnetic resonance imaging has undergone considerable histologic validation to link imaging features to indicators of plaque instability, including plaque burden, intraplaque hemorrhage, fibrous cap disruption, lipid rich necrotic core, and calcification. Recently introduced imaging technologies, especially those focused on three-dimensional imaging sequences, are now poised for integration into the clinical workup of patients with suspected carotid atherosclerosis. The purpose of this article is to review the carotid plaque magnetic resonance imaging techniques that are most ready for integration into the clinic.     

Floating thrombus as a marker of unstable atheromatous carotid plaque

Floating thrombus in a carotid artery is an uncommon pathology with a high risk of embolism. We present three patients diagnosed with acute stroke, with a floating thrombus complicating an atheromatous plaque, who were treated with anticoagulants and statins. Although two patients had satisfactory results, one patient suffered a stroke related to plaque progression nearly 3 years after initial presentation. Medical treatment seems to be a good initial option, although late cerebral ischemic complications may be seen due to carotid plaque instability. Delayed carotid endarterectomy or stenting should be considered in cases with subsequent plaque progression.     

The influence of repeated carotid plaque hemorrhages on the production of cerebrovascular symptoms

Single carotid intraplaque hemorrhage has been related to the occurrence of cerebrovascular ischemic symptoms. We were unable to reproduce these findings; therefore, our patient population was reinvestigated to ascertain the importance of repeated plaque hemorrhages and their possible relationship to the production of neurologic symptoms. Eighty-five consecutive patients underwent 95 carotid endarterectomies. Plaques were separated into three groups: those from patients with lateralizing symptoms, nonlateralizing symptoms, and no symptoms. All the plaques were inspected microscopically for evidence of hemorrhage, specifically, repeated hemorrhages. Repeated hemorrhages were found in 29 of 44 plaques (66%) in the lateralizing symptom group, 6 of 19 (32%) in the nonlateralizing symptom group, and 12 of 32 (37%) in the no symptom group. We conclude that repeated rather than single intraplaque hemorrhage is the critical factor related to the production of specific cerebrovascular ischemic symptoms.     

Angiogenesis in atherosclerotic plaque obtained from carotid endarterectomy: association between symptomatology and plaque morphology

Carotid plaque with hemorrhage leads to cerebral embolism and ischemic stroke. Plaque angiogenesis and angiogenetic factors such as vascular endothelial growth factor (VEGF) are critical in the progression of atherosclerotic carotid plaque and intraplaque hemorrhage. The correlation between plaque angiogenesis and presence of clinical symptoms was studied in 41 specimens obtained during carotid endarterectomy from 20 symptomatic and 21 asymptomatic patients treated for carotid artery stenosis. Histological findings using hematoxylin-eosin and immunohistochemical staining against von Willebrand factor and VEGF were examined. Intraplaque hemorrhage, calcification, necrosis, and invasion of foam cells were frequently observed in the carotid plaques from symptomatic patients compared with asymptomatic patients. Higher microvessel density was found in the carotid plaques with necrosis and invasion of foam cells compared with plaques without necrosis and/or foam cell invasion, and higher expression of VEGF was found from symptomatic patients compared with asymptomatic patents. These results suggest that plaque angiogenesis and higher level of VEGF expression may enhance the progression of ischemic symptoms in patients with carotid artery stenosis. Invasive macrophages in the plaque of symptomatic patients increase levels of VEGF and might enhance plaque angiogenesis and atherosclerosis progression.     

颈动脉外翻内膜剥脱术治疗颈动脉硬化狭窄

目的观察颈动脉外翻内膜剥脱术治疗颈动脉狭窄的疗效。方法24例颈动脉硬化狭窄患者,其中18例有慢性或一过性脑缺血症状,6例无症状;术前均行彩色超声、数字减影动脉造影(DSA)或CT和MRA扫描检查,颈动脉狭窄程度65％～95％;在颈丛麻醉下行颈动脉外翻内膜剥脱术,手术要点是于颈动脉分叉处斜形切断颈内动脉,外翻颈内动脉剥除有粥样斑块的内膜,同时从颈总动脉切口剥除颈总动脉和颈外动脉增厚的内膜。结果全组无手术死亡,术后随访3～20个月,临床症状均有不同程度改善,一过性脑缺血症状消失,4例仍有轻度慢性脑缺血症状。术后行脑部多普勒超声检查,22例脑部供血有明显改善。结论颈动脉外翻内膜剥脱术是一种安全、有效和合理的手术方式。     

Natural history of asymptomatic carotid plaque. Five year follow-up study

A prospective analysis of 296 carotid arteries in 293 asymptomatic patients was undertaken using real-time B-mode ultrasonography. All patients had carotid bifurcation disease and were followed for an average of 46 months. The endpoint for follow-up was a transient ischemic attack or stroke. Patients were categorized according to degree of stenosis (greater or less than 75 percent) and morphologic plaque characteristics (calcified, dense, or soft). Patients with hemodynamically significant stenosis were at greater risk of transient ischemic attack or stroke than their counterparts with less than 75 percent stenosis. However, even patients with less than 75 percent stenosis were at risk if the plaque was less organized (dense or soft). Patients with hemodynamically significant stenosis and morphologically soft plaque were at the greatest risk of transient ischemic attack or stroke. Those patients with calcified plaque and less than 75 percent stenosis had the lowest risk of transient ischemic attack or stroke. Morphologic plaque characteristics, as well as degree of stenosis, is important in determining which patients are candidates for carotid endarterectomy.     

Carotid plaque morphology correlates with presenting symptomatology

Purpose: In carotid artery disease, correlation of carotid plaque morphology with the patient's presenting symptoms has drawn conflicting conclusions. The purpose of this series was to correlate carotid plaque characteristics with the presenting symptoms from a large cohort of patients who underwent operation for carotid artery disease. Methods: From a series of 1252 consecutive patients who underwent carotid endarterectomy, presenting symptoms were divided into three groups: transiently symptomatic (transient ischemic attack [TIA] or amaurosis fugax), prior stroke, and asymptomatic. Plaque characteristics, including ulceration, intraplaque hemorrhage, and degree of stenosis, were recorded prospectively for 1008 procedures. All endarterectomy specimens were inspected during the procedure, and plaque characteristics were recorded immediately after operation. Results: There was a higher incidence of plaque ulceration in the transiently symptomatic and prior stroke groups (391 of 508 [77%] and 91 of 115 [79%]) than in the asymptomatic cohort (231 of 385 [60%]; p< 0.0001, χ² test). There was no significant difference in the incidence of plaque hemorrhage between the transiently symptomatic and prior stroke patients compared with the asymptomatic patients. There was no statistical difference for ulcerated plaque or plaque hemorrhage between the transiently symptomatic and prior stroke groups. Intraplaque hemorrhage occurred more frequently in patients with high-grade stenosis (90% to 99%) than in those with less than 90% stenosis (202 of 299 [68%] versus 97 of 299 [32%]; p = 0.01, χ² test). Conclusions: On gross examination of the carotid specimen in the operating room, plaque ulceration correlates with an initial presentation of amaurosis fugax, TIA, or prior stroke compared with patients operated on for asymptomatic disease. The presence of intraplaque hemorrhage is associated with more advanced stenosis of the internal carotid artery. These findings suggest that plaque morphology does play an important role in the presentation of carotid artery disease. (J Vasc Surg 1998;27:872-9.)     

Fibrous cap thickness and smooth muscle cell apoptosis in high-grade carotid artery stenosis.

OBJECTIVE: There is growing evidence that, in high-grade internal carotid artery (ICA) stenosis, continuous fibrous cap thinning is not mandatory for plaque rupture and symptom development. The possibility that smooth muscle cell (SMC) apoptosis is involved in loss of fibrous cap volume has only been examined in a limited number of patients with high grade carotid artery stenosis. METHODS: Endarterectomy specimens from n = 38 consecutive patients undergoing surgery for high-grade ICA stenosis (> or = 70%) were transversely sectioned at 2 mm intervals. Plaque instability was defined clinically, by a history of recent ischemic symptoms (< 60 days before surgery; n = 19) attributable to the stenosis, or histopathologically by the presence of plaque rupture (n = 14). Detailed morphometric analyses of the fibrous cap was based on routine stains; for DNA in situ end labeling the TUNEL technique was used. SMCs were identified by immunostaining for SMC actin. RESULTS: We found no significant difference between symptomatic/asymptomatic or ruptured/unruptured plaque with respect to various morphometric measures of the fibrous cap (i.e. mean area, number of plaque sections with fibrous cap, necrotic core-to-lumen distance at its thinnest or thickest part). The mean (+/- SD) apoptotic SMCs per thousand within the fibrous cap was significantly higher in symptomatic vs. asymptomatic (64.53 +/- 77.3 vs. 6.71 +/- 11.9; P<0.001) but not in ruptured plaques (43.3 +/- 64.4 vs. 30.1 +/- 60.9; P=0.117). CONCLUSIONS: These data suggest that continuous thinning of the fibrous cap is not an essential prerequisite for plaque rupture in ICA stenosis. Symptomatic, but not ruptured plaque, were associated with the highest number of apoptotic SMC. Thus, it seems unlikely that SMC apoptosis promotes plaque rupture by fibrous cap thinning.     

Clinical relevance of intraplaque hemorrhage in the internal carotid artery.

In this study the correlation between hemispherical ischemic symptoms and the presence of intraplaque hemorrhage in carotid plaques has been evaluated. 38 patients who had undergone carotid endarterectomy were examined clinically and the specimens obtained from operation were studied morphologically. The patients were divided into two groups, asymptomatic and symptomatic regarding the territory of the supplying carotid artery. The presence of intraplaque hemorrhage, shown by Ladewig's Trichrom stain, as well as evidence of iron, immunohistochemical stain of hemoglobin and native fluorescence microscopy was noted, and, according to their extension, classified into three degrees. As a result, there was neither a correlation between history of ischemic brain symptoms and the presence of intraplaque hemorrhage, nor between clinical symptoms and extension of hemorrhage. The plaques were high degree stenotic (greater than 80%) in most of the patients and showed various degenerative changes. In 97% of all plaques with hemorrhages surface defects were seen. Our results confirm that intraplaque hemorrhage is one out of a series of pathological events which occurs during advanced atherosclerosis. Blood inflow from the lumen through an already damaged plaque surface is a common event and a correlation with the onset of symptoms is unlikely.     

High-risk carotid plaque: lessons learned from histopathology

The pathophysiology and natural history of atherosclerotic carotid disease is predicated on a more extensive knowledge of lesion progression gained in the studies conducted in the coronary arteries, and these will be reviewed. While the precise sequence of lesion progression leading to carotid plaque vulnerability and cerebrovascular events remain less well understood, specific early and more advanced progressive lesion morphologies associated with stroke risk have been characterized. Of late, there has been a conscious effort for stroke prevention in symptomatic and asymptomatic patients to move beyond luminal stenosis as the only guidance to predict future cerebrovascular events. Driving this strategy are recent advances in medical imaging modalities to assess carotid atherosclerosis vulnerability particularly involving molecular imaging, which is now positioned at the forefront to provide a more detailed and mechanistic assessment of stroke risk. As such, we will spotlight the pathology of high-risk carotid plaques in patients with symptomatic and asymptomatic carotid disease with further reference into more recent mechanistic insights involving a recognized macrophage-mediated inflammatory change, intraplaque neoangiogenesis/hemorrhage, hypoxia, and microcalcification, as potential morphologic indicators of stroke risk.     

Gelatinases [Matrix Metalloproteinase-2 (MMP-2) and MMP-9] Induce Carotid Plaque Instability But Their Systemic Levels Are Not Predictive of Local Events

Matrix metalloproteinases (MMPs) appear to play a central role in atherosclerotic plaque remodeling; however, the relationship of increased MMP levels in inducing carotid plaque instability remains controversial. We investigated whether gelatinases (MMP-2 and MMP-9) are implicated in carotid intraplaque hemorrhage and whether their serum levels may predict local carotid events. Nineteen carotid specimens obtained by endarterectomy of 18 patients were studied. The presence of gross intraplaque hemorrhage was recorded before plaque removal and quantification of MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) in extracts from (1) the more stenotic area of the plaque, (2) the periphery of the plaque, and (3) serum was performed by enzyme-linked immunosorbent assay. MMP-9 levels measured in extracts from the most stenotic area were significantly higher in patients with intraplaque hemorrhage (p = 0.007); however, serum levels showed no difference, while those taken from the periphery of the lesion were also increased but did not reach a statistically significant level (p = 0.06). An increase in MMP-2 values was observed in the periphery of the lesion (p = 0.04) in patients with intraplaque hemorrhage. TIMP-1 levels showed no difference between the two groups regardless of the presence or absence of intraplaque hemorrhage. No significant differences in MMP levels were observed between symptomatic and asymptomatic patients. Increased levels of MMPs, particularly MMP-9, have been implicated in carotid intraplaque hemorrhage without their serum levels being predictive of local events.     

David M. Hume Memorial Lecture. An overview of the stroke problem in the carotid territory

In a review of 1,000 carotid endarterectomies performed over a 20 year period, there was relief of transient ischemic attacks in approximately 85% of patients, an operative mortality of 1.3%, due almost exclusively to myocardial infarction, and a recurrent stenosis rate of 3.1%. Coexisting cardiac disease constitutes the greatest operative hazard. Continuous electroencephalographic monitoring is a reliable method of detecting inadequate cerebral perfusion during carotid cross clamping and for the selective use of a temporary inlying carotid shunt. An atherosclerotic plaque in the carotid system constitutes a greater risk than elsewhere in the peripheral arterial system and should not be considered an innocent lesion. Prophylactic carotid endarterectomy can be performed with almost no mortality and morbidity. Antiplatelet agents, while useful in reducing the incidence of transient ischemic attacks, do not seem to provide equal protection against stroke and death from stroke.