Eija Saimanen

Cerebral Hemodynamics in Asymptomatic and Symptomatic Patients With High-Grade Carotid Stenosis Undergoing Carotid Endarterectomy

Background and Purpose— Asymptomatic patients with carotid stenosis benefit less from carotid endarterectomy (CEA) than symptomatic patients because the risk of embolic events is lower, but it is not known whether the hemodynamic effect of CEA is different between the groups. We evaluated hemodynamics of symptomatic and asymptomatic patient groups before and after CEA. Methods— Forty-six independent patients with a unilateral high-grade carotid stenosis, 23 asymptomatic and 23 symptomatic, underwent dynamic susceptibility contrast MRI (DSC-MRI) and transcranial Doppler ultrasound (TCD) evaluation before CEA and 3 and 100 days afterward. Quantitative perfusion parameters were calculated separately in selected regions of white and gray matter and watershed regions in each hemisphere, and mean transit time (MTT) maps were assessed visually by 2 independent observers. Vasomotor reactivity was determined with breath-holding index and flow impedance with pulsatility index ipsilaterally. Results— In contrast to the asymptomatic carotid stenosis group, symptomatic carotid stenosis patients had preoperatively increased MTT and lower cerebral blood flow values in the ipsilateral hemisphere, more in white matter and watershed regions than in gray matter. Visually detected perfusion deficits were associated with symptomatic status. The interhemispheric asymmetries were abolished by CEA. The improving trend over time was greater in the symptomatic carotid stenosis group and was best seen in MTT. On TCD, pulsatility index was lower in symptomatic carotid stenosis patients preoperatively, with no postoperative difference, whereas the breath-holding index improved only in the symptomatic carotid stenosis group after CEA. Conclusions— Patients with asymptomatic and symptomatic carotid stenosis differ significantly by means of DSC-MRI and TCD before and in response to CEA.

Infrarenal endoluminal bifurcated stent graft infected with Listeria monocytogenes

Prosthetic graft infection as a result of Listeria monocytogenes is an extremely rare event that recently occurred in a 77-year-old man who underwent endoluminal stent grafting for infrarenal abdominal aortic aneurysm. The infected aortic endoluminal prosthesis was removed by means of en bloc resection of the aneurysm and contained endograft with in situ aortoiliac reconstruction. At the 10-month follow-up examination, the patient was well and had no signs of infection.

Microarray Analysis Reveals Overexpression of CD163 and HO-1 in Symptomatic Carotid Plaques

Objective—We studied by microarray analysis whether symptomatic and asymptomatic carotid plaques from the same patient differ in gene expression and whether the same changes are present in an independent sample set. Methods and Results—Carotid plaques from four patients with bilateral high-grade stenosis, one being symptomatic and the other asymptomatic, were analyzed on Affymetrix U95Av2 arrays. 33 genes showed >1.5-fold change between symptomatic and asymptomatic plaques in an intraindividual comparison with FDR ranging from 0.28 to 0.40. Three genes involved in iron-heme homeostasis, CD163, HO-1, and transferrin receptor, were further analyzed in 40 independent plaques. HO-1 (fold-change 1.93, 95%CI 1.04 to 3.94, P=0.040) and CD163 (1.58, 1.11 to 2.40, P=0.013) mRNAs were again induced, and also HO-1 protein was overexpressed in symptomatic plaques (4.38, 1.54 to 12.20, P=0.024). The expression of HO-1 and CD163 correlated with tissue iron content but iron itself was not associated with the symptom status. Conclusions—Symptomatic plaques show overexpression of CD163 and HO-1 both in intraindividual and interindividual comparison. Their expression correlates with iron deposits but asymptomatic and symptomatic plaques from isolated patients do not differ in macroscopic hemorrhages or iron deposits. We suggest that symptomatic plaques show a more pronounced induction of CD163 and HO-1 in response to plaque hemorrhages.

Adipophilin Expression Is Increased in Symptomatic Carotid Atherosclerosis: Correlation With Red Blood Cells and Cholesterol Crystals

Background and Purpose— Adipophilin is an adipose differentiation–related protein expressed in lipid-containing cells. Using DNA microarray analysis, we previously found the adipophilin gene (ADFP) to be overexpressed in symptomatic carotid plaques (CP). This led us to further examine the role of adipophilin in carotid atherosclerosis relative to symptom status. Methods— Ninety-eight high-grade (>70%) CPs were obtained in carotid endarterectomy. The relative expression of ADFP mRNA was measured by quantitative real-time RT-PCR, and the relative amount of adipophilin protein was quantified with Western blotting. Detailed topographical correlations with extravasated red blood cells and extracellular cholesterol crystals were obtained by means of immunohistochemistry. Results— The relative expression of ADFP mRNA was increased in symptomatic compared with asymptomatic CPs at both the mRNA level (1.82±0.19[SE] versus 1.25±0.15, P=0.012) and the protein level (1.04±0.23 versus 0.46±0.14, P=0.043). Adipophilin colocalized with macrophage foam cells, extravasated red blood cells (P<0.0001), and cholesterol crystals (P<0.0001), and its expression associated with macroscopic ulceration of CP (P<0.0001). Conclusions— Intraplaque hemorrhages may contribute to intracellular lipid accumulation and consequent adipophilin expression. Because adipophilin blocks cholesterol efflux from lipid-laden cells, they may die and develop a necrotic lipid core, thereby destabilizing the plaque.

Adhesion molecule expression in symptomatic and asymptomatic carotid stenosis

Background: Prior studies have suggested a central role for cellular adhesion molecules (CAMs) in the pathophysiology and symptoms of atherosclerotic carotid plaques (CPs). Objective: This study examined the role of CAMs in symptom generation in patients with advanced carotid artery disease. Methods: Ninety-two consecutive patients underwent carotid endarterectomy, six for both sides (54 symptomatic and 41 asymptomatic CPs). Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and E-selectin were immunostained in fresh-frozen CP specimens and examined semiquantitatively in the endothelium and intima-media. Plasma concentrations of soluble ICAM-1 and sVCAM-1 were analyzed by ELISA. Results: Endothelial expression of ICAM-1, VCAM-1, P-selectin, and E-selectin did not differ between symptomatic and asymptomatic CPs, but endothelial ICAM-1 was associated with serum sensitized C-reactive protein levels (p = 0.026). However, there was less ICAM-1 expression in the intima-media of the symptomatic CPs (p = 0.022), and there was a similar, but nonsignificant tendency for VCAM-1. Soluble ICAM-1 and soluble VCAM-1 were not associated with the symptom status. Conclusions: In contrast to earlier studies, it was found that symptomatic carotid disease is not associated with increased expression of adhesion molecules in the endothelium of advanced carotid plaques or in circulation. Rather, there was less expression of adhesion molecules in the intima-media of symptomatic carotid plaques.

Brain diffusion changes in carotid occlusive disease treated with endarterectomy

Background: Patients with unilateral high-grade carotid stenosis or occlusion have been reported to have more leukoaraiosis and ischemic lesions in ipsilateral than in contralateral cerebral hemisphere. The lesions alter apparent diffusion coefficient (ADC) values in diffusion-weighted MRI (DWI). The overall effects of carotid endarterectomy on ADC values have not yet been explored. Objectives: To find out whether 1) average ADC (ADCav) values differed between hemispheres, 2) diffusion changes induced by carotid endarterectomy could be detected in brain tissue with serial DWI, and 3) patients with asymptomatic carotid stenosis differed from patients with a symptomatic stenosis. Methods: Forty-five patients (22 with asymptomatic carotid stenosis and 23 with symptomatic carotid stenosis) with unilateral high-grade carotid stenosis underwent DWI before carotid endarterectomy and 3 and 100 days afterward, and 45 age- and sex-matched healthy control subjects were imaged once. We evaluated ADCav values in normal-appearing gray and white matter, watershed regions (WsR), and thalamus. Results: ADCav values of ipsilateral white matter and WsR were higher than those of contralateral white matter and WsR, both being higher than in white matter and WsR of control subjects. After carotid endarterectomy, these differences were diminished, but the levels remained higher than in controls. ADCav values of gray matter and thalamus remained unaffected. Asymptomatic carotid stenosis and symptomatic carotid stenosis patient groups did not differ from each other. Conclusions: Carotid stenosis has an effect on diffusion in the white matter of the ipsilateral hemisphere, and it is partly reversible by carotid endarterectomy. The finding may be associated with leukoaraiotic development (“preleukoaraiosis”).

Carotid Plaque Mast Cells Associate with Atherogenic Serum Lipids, High Grade Carotid Stenosis and Symptomatic Carotid Artery Disease

Objective: Increased numbers of mast cells (MCs) are present in ruptured coronary plaques, suggesting to play a role in acute coronary syndromes. We evaluated the distribution densities of MCs, macrophages and T cells in carotid plaques and correlated these findings to stroke risk factors as well as history of stroke or TIA. Methods and Results: Seventy-eight carotid samples from 75 patients (16 plaques from asymptomatic patients and 62 from patients with recent ischemic symptoms) undergoing carotid endarterectomy with an internal carotid stenosis >70% that were immunostained and quantified for MCs, macrophages and T cells. The MC distribution density showed positive correlation with the degree of carotid stenosis (p = 0.012), serum levels of total cholesterol (p = 0.021), LDL cholesterol (p = 0.013) and triglycerides (p = 0.005), and an inverse correlation with serum HDL cholesterol levels (p = 0.001). The average MC density (p = 0.023), but not the macrophage (p = 0.58) or T cell (p = 0.74) density, was higher in the symptomatic than in the asymptomatic patients. In a comparison of plaques ipsilateral and contralateral to the thromboembolic event, the densities of the three types of inflammatory cells were similar. Conclusions: Increased MC distribution density is associated with an atherogenic serum lipid profile, high-grade carotid artery stenosis and symptomatic carotid artery disease. These findings suggest a potential involvement of MCs in the pathophysiology of carotid artery stenosis.

Gene expression differences between stroke-associated and asymptomatic carotid plaques

Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2-fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization.

The Effect of Severe Carotid Occlusive Disease and Its Surgical Treatment on Cognitive Functions of the Brain.

Surgery of a high-grade carotid stenosis is evidence-based stroke prevention. Also cognitive effects are reported after carotid endarterectomy (CEA): both deterioration and improvement, the former attributed to perioperative complications and the latter often to learning effect. By imaging, brain perfusion and diffusion changes were shown in subjects with a high-grade stenosis undergoing CEA. We wanted to find out if the cognition of patients undergoing CEA display postoperative worsening or true improvement in association with findings in serial MR imaging. The patients had a poorer overall cognition than healthy matched controls. The cerebral hemisphere ipsilateral to the stenosis had higher diffusion and more sluggish perfusion leading to perfusion deficits. These asymmetries were abolished by CEA. Postoperatively, the patients showed a trend for cognitive worsening, most often attentional, but over months, the group performance improved similarly to the controls. Still, lower baseline perfusion was associated with a greater cognitive improvement, most clearly in executive functions. Consequently, despite the risk for transient decline, true cognitive benefit by CEA seems possible.

Association of the fibrinolytic system and hemorheology with symptoms in patients with carotid occlusive disease.

Background and Objectives: The risk of stroke caused by a symptomatic high-grade carotid stenosis (CS) is high. Disturbed balance between the procoagulant and fibrinolytic activity in blood associated with unfavorable hemorheology could render CS symptomatic. We wanted to assess whether hemostatic and fibrinolytic plasma markers as well as basic indicators of hemorheology differentiate asymptomatic and symptomatic patients with a high-grade CS and whether they are associated with the macroscopic appearance of the plaque and the rate of microembolization. Methods: We recruited 92 consecutive consenting patients referred to the neurological or the surgical department of our university teaching hospital for treatment of their high-grade CS. Blood samples were collected before surgery for determination of prothrombin fragments F1 and 2, thrombin-antithrombin complex, tissue-type plasminogen activator (tPA) activity and antigen, plasminogen activator inhibitor-1 (PAI-1) activity and antigen, D-dimer, homocysteine, fibrinogen, in plasma, and hematocrit in blood, and the patients underwent transcranial Doppler ultrasonology for evaluation of microembolic signals (MES). Results: Patients with symptomatic plaques had higher hematocrit levels (p = 0.04), as well as trends for higher tPA antigen and MES rate (p = 0.07). Hematocrit, tPA antigen, and PAI-1 antigen and activity were positively correlated with the degree of stenosis. Ulceration was more common in symptomatic plaques but did not reflect variables of hemostasis or fibrinolysis. In multivariate analysis, tPA antigen and hematocrit were risk factors for a symptomatic high-grade stenosis. Conclusion: Mediators of fibrinolysis and unfavorable hemorheology may contribute to the development of a symptomatic disease in patients with a high-grade CS.