Peter Heider

Differences in number, size and location of intracranial microembolic lesions after surgical versus endovascular treatment without protection device of carotid artery stenosis.

Abstract.Background and purpose:The benefit of carotid endarterectomy in symptomatic high-grade stenosis has long been proven. The role of angioplasty as an alternative is still a matter of debate. We compared the occurrence of intraprocedural microembolic signals and ischemic lesions between carotid endarterectomy (CEA) and carotid angioplasty with stent placement (CAS) without a protection device.Methods:88 patients who underwent a CEA and 41 patients who underwent CAS were prospectively investigated. One day before and after the intervention diffusion weighted MRI-studies were obtained. In 21 CEA and 18 CAS patients transcranial Doppler (TCD) monitoring was performed during the procedure to detect microembolic signals (MES).Results:DWI-lesions could be detected after intervention in 17% of the CEA patients compared with 54% of the CAS patients (p<0.005). The median lesion volume was 0.08cm3 in the CEA group and 0.02cm3 in the CAS group (p<0.001). Ischemic complications consisted of 2 strokes (2.3%) with symptoms lasting more than seven days in the CEA group and 1 stroke (2.4 %) in the CAS group. The median number of MES in the CEA group was 17 versus 61 in the CAS group (p<0.001). No significant correlation was found between the total number of MES and ischemic lesions in either group.Conclusion:A larger number of emboligenic particles with smaller volume is detached during CAS. Additionally DWI lesions were observed in different territories after CAS but not after CEA. Conventional TCD emboli detection is not useful to compare interventional therapies of the carotid arteries.

Microembolic Signals Detected by Transcranial Doppler Sonography During Carotid Endarterectomy and Correlation With Serial Diffusion-Weighted Imaging

Background and Purpose— Embolic events are a major cause for procedure-related strokes after carotid endarterectomy (CEA). Transcranial Doppler sonography can reveal embolic events as microembolic signals (MES) during CEA. MES during declamping and shunting are frequently detected. MES during shunting are rare and known to be correlated with the neurological outcome of the patient. In the present study, we analyzed the occurrence of MES within different stages of CEA and whether MES within those stages were correlated with cerebral ischemia, as detected by diffusion-weighted imaging (DWI), and brain infarction, as detected by contrast-enhanced MRI. Methods— Thirty-three patients were monitored intraoperatively for MES using transcranial Doppler sonography. DWI was performed within 24 hours before and after surgery. Positive postoperative DWI led to reexamination with contrast-enhanced T1-MRI 7 to 10 days after CEA for detection of cerebral infarction. Results— MES were detected in 32 of 33 patients. The highest number of MES was found during shunting and declamping. A significant correlation was found between MES and DWI-lesions during dissection. A significant correlation was found between MES during dissection and shunting, and nonsignificant correlation was found between MES and the occurrence of cerebral infarction. Conclusion— MES could be regularly detected during CEA. Dissection and shunting seem to be the most vulnerable stages of the procedure.

PET/CT Imaging of Integrin αvβ3 Expression in Human Carotid Atherosclerosis

OBJECTIVES The goal of this study was to evaluate the feasibility of [(18)F]Galacto-RGD positron emission tomography (PET)/computed tomography (CT) imaging of αvβ3 expression in human carotid plaques. BACKGROUND The integrin αvβ3 is expressed by macrophages and angiogenic endothelial cells in atherosclerotic lesions and thus is a marker of plaque inflammation and, potentially, of plaque vulnerability. [(18)F]Galacto-RGD is a PET tracer binding specifically to αvβ3. Therefore, [(18)F]Galacto-RGD PET/CT imaging of αvβ3 expression in human carotid plaques might provide a novel noninvasive biomarker of plaque vulnerability. METHODS [(18)F]Galacto-RGD PET/CT imaging was performed in 10 patients with high-grade carotid artery stenosis scheduled for carotid endarterectomy. Tracer uptake was measured in the stenotic areas of the carotid arteries, as well as on the contralateral side, and was corrected for blood pool activity, measured in the distal common carotid artery (target-to-background [TB] ratio). TB ratio was correlated with immunohistochemistry of αvβ3 expression (LM609), macrophage density (CD68), and microvessel density (CD31) of the surgical specimen. In addition, ex vivo autoradiography of the surgical specimen with [(18)F]Galacto-RGD and competition experiments with an unlabeled αvβ3-specific RGD peptide were performed. RESULTS [(18)F]Galacto-RGD PET/CT showed significantly higher TB ratios in stenotic areas compared with nonstenotic areas (p = 0.01). TB ratios correlated significantly with αvβ3 expression (R = 0.787, p = 0.026) and intensity of ex vivo autoradiography (R = 0.733, p = 0.038). Binding to atherosclerotic plaques was efficiently blocked in ex vivo competition experiments. A weak-to-moderate correlation was found with macrophage density (R = 0.367, p = 0.299) and microvessel density (R = 0.479, p = 0.176), which did not reach statistical significance. CONCLUSIONS [(18)F]Galacto-RGD PET/CT shows specific tracer accumulation in human atherosclerotic carotid plaques, which correlates with αvβ3 expression. Based on these initial data, larger prospective studies are now warranted to evaluate the potential of molecular imaging of αvβ3 expression for assessment of plaque inflammation in patients.

MRI plaque imaging reveals high-risk carotid plaques especially in diabetic patients irrespective of the degree of stenosis

BackgroundPlaque imaging based on magnetic resonance imaging (MRI) represents a new modality for risk assessment in atherosclerosis. It allows classification of carotid plaques in high-risk and low-risk lesion types (I-VIII). Type 2 diabetes mellitus (DM 2) represents a known risk factor for atherosclerosis, but its specific influence on plaque vulnerability is not fully understood. This study investigates whether MRI-plaque imaging can reveal differences in carotid plaque features of diabetic patients compared to nondiabetics.Methods191 patients with moderate to high-grade carotid artery stenosis were enrolled after written informed consent was obtained. Each patient underwent MRI-plaque imaging using a 1.5-T scanner with phased-array carotid coils. The carotid plaques were classified as lesion types I-VIII according to the MRI-modified AHA criteria. For 36 patients histology data was available.ResultsEleven patients were excluded because of insufficient MR-image quality. DM 2 was diagnosed in 51 patients (28.3%). Concordance between histology and MRI-classification was 91.7% (33/36) and showed a Cohens kappa value of 0.81 with a 95% CI of 0.98-1.15. MRI-defined high-risk lesion types were overrepresented in diabetic patients (n = 29; 56.8%). Multiple logistic regression analysis revealed association between DM 2 and MRI-defined high-risk lesion types (OR 2.59; 95% CI [1.15-5.81]), independent of the degree of stenosis.ConclusionDM 2 seems to represent a predictor for the development of vulnerable carotid plaques irrespective of the degree of stenosis and other risk factors. MRI-plaque imaging represents a new tool for risk stratification of diabetic patients.See Commentary: http://www.biomedcentral.com/1741-7015/8/78/abstract

Fractalkine Is Expressed in Early and Advanced Atherosclerotic Lesions and Supports Monocyte Recruitment via CX3CR1

Fractalkine (CX3CL1, FKN) is expressed in the inflamed vascular wall and absence of FKN reduces atherogenesis. Whether FKN is expressed throughout all stages of atherosclerotic disease and whether it directly contributes to monocyte recruitment to atherosclerotic lesions is not known. We collected human atherosclerotic plaque material and blood samples from patients with carotid artery disease undergoing endarterectomy. Plaques were analyzed by immunohistochemistry and qPCR. We found that FKN is expressed at all stages of atherosclerotic lesion formation, and that the number of FKN-expressing cells positively correlates with the number of CX3CR1-positive cells in human carotid artery plaques. In the circulation, soluble FKN levels are significantly elevated in the presence of high-grade (sub-occlusive) stenosis. To determine the role of the FKN-CX3CR1 axis for monocyte adhesion in vivo we then performed intravital videofluorescence microscopy of the carotid artery in ApoE−/− mice. Notably, FKN-CX3CR1 interactions are critical for recruitment of circulating monocytes to the injured atherosclerotic vascular wall. Thus, this chemokine dyad could represent an attractive target for anti-atherosclerotic strategies.

MRI Plaque Imaging Detects Carotid Plaques with a High Risk for Future Cerebrovascular Events in Asymptomatic Patients

Purpose The aim of this study was to investigate prospectively whether MRI plaque imaging can identify patients with asymptomatic carotid artery stenosis who have an increased risk for future cerebral events. MRI plaque imaging allows categorization of carotid stenosis into different lesion types (I–VIII). Within these lesion types, lesion types IV–V and VI are regarded as rupture-prone plaques, whereas the other lesion types represent stable ones. Methods Eighty-three consecutive patients (45 male (54.2%); age 54–88 years (mean 73.2 years)) presenting with an asymptomatic carotid stenosis of 50–99% according to ECST-criteria were recruited. Patients were imaged with a 1.5-T scanner. T1-, T2-, time-of-flight-, and proton-density weighted studies were performed. The carotid plaques were classified as lesion type I–VIII. Clinical endpoints were ischemic stroke, TIA or amaurosis fugax. Survival analysis and log rank test were used to ascertain statistical significance. Results Six out of 83 patients (7.2%) were excluded: 4 patients had insufficient MR image quality; 1 patient was lost-to-follow-up; 1 patient died shortly after the baseline MRI plaque imaging. The following results were obtained by analyzing the remaining 77 patients. The mean time of follow-up was 41.1 months. During follow-up, n = 9 (11.7%) ipsilateral ischemic cerebrovascular events occurred. Only patients presenting with the high-risk lesion types IV–V and VI developed an ipsilateral cerebrovascular event versus none of the patients presenting with the stable lesion types III, VII, and VIII (n = 9 (11.7%) vs. n = 0 (0%) during follow-up). Event-free survival was higher among patients with the MRI-defined stable lesion types (III, VII, and VIII) than in patients with the high-risk lesion types (IV–V and VI) (log rank test P<0.0001). Conclusions MRI plaque imaging has the potential to identify patients with asymptomatic carotid stenosis who are particularly at risk of developing future cerebral ischemia. MRI could improve selection criteria for invasive therapy in the future.

Impact of chronic kidney disease on carotid plaque vulnerability

OBJECTIVE Little is known about the effect of chronic kidney disease (CKD) on plaque morphology in cerebral vessels. We therefore analyzed plaque composition and metabolic and chemical parameters with regard to clinical outcome in patients with advanced carotid artery stenosis (>70%) and normal or impaired renal function. METHODS Carotid endarterectomy plaques were collected from 114 patients, 51 with CKD and 63 without CKD (mean estimated glomerular filtration rate, 49 ± 9 vs 88 ± 14 mL/min), and analyzed by histology and immunohistochemistry. Serum levels of matrix metalloproteinases (MMP-1, -2, -3, -7, -8, and -9), calcium, phosphate, parathyroid hormone, fetuin-A, osteoprotegerin, and inflammatory factors, including fibrinogen, and high-sensitive C-reactive protein (hsCRP) were measured by appropriate enzyme-linked immunosorbent assay. RESULTS Compared with patients without CKD, patients with CKD had significantly more early-stage (11.2% vs 2.8%, P = .002) and end-stage (7.4% vs 0.2%, P = .036) calcification, unstable (50.8% vs 20.4%, P = .001) and ruptured (53.1% vs 32.8%, P = .035) lesions, and a significantly lower amount of collagenous fibers (39.2% vs 54.6%, P = .001). Serum samples of CKD patients had significantly enhanced levels of fibrinogen (393 ± 88 vs 331 ± 60 mg/dL, P = .018), hsCRP (1.7 ± 2.9 vs 0.8 ± 0.9 mg/dL; P = .042), parathyroid hormone (47.3 ± 24.1 vs 32.8 ± 12.2 ng/L, P = .010), fetuin-A (0.21 ± 0.05 vs 0.18 ± 0.04 mg/mL, P = .039), and MMP-7 (13.0 ± 5.3 vs 8.3 ± 3.0 ng/mL; P < 0.001). The incidence of cerebrovascular events >6 months before carotid surgery was significantly increased in CKD patients (84.0% vs 26.2% P < .001). CONCLUSIONS In patients with CKD and advanced carotid artery stenosis, morphologic changes in plaque composition may contribute to plaque vulnerability and consequently to the risk of cerebrovascular events. Furthermore, relevant serum markers of inflammation, vascular calcification, and vessel wall degradation might be an indication of stroke risk in CKD patients.

The CX3C Chemokine Fractalkine Induces Vascular Dysfunction by Generation of Superoxide Anions

Objective—The chemokine fractalkine activates platelets and induces leukocyte adhesion to the endothelium. Expression of fractalkine and its receptor, CX3CR1, is elevated in coronary artery disease. We assessed the effects of fractalkine on vascular function in isolated rat aorta. Methods and Results—CX3CR1 expression was demonstrated in rat aortic endothelial and smooth muscle cells by immunohistochemistry, Western blot, and polymerase chain reaction (PCR). Fractalkine (up to 1 &mgr;g/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 &mgr;g/mL) for 5 minutes did not affect vascular reactivity. Pretreatment of isolated rat aortic rings with fractalkine for 2 hours impaired acetylcholine-induced nitric oxide (NO)-mediated relaxation after preconstriction with phenylephrine in a concentration-dependent manner. The concentration response to the NO donor DEA-NONOate was significantly shifted to the right. The radical scavenger tiron normalized the attenuated acetylcholine-induced relaxation after fractalkine incubation. Aortic superoxide formation was enhanced by fractalkine, which was inhibited by diphenyleneiodonium but not by inhibitors of xanthine oxidase or NO synthase. Conclusion—In addition to its role as a chemokine and adhesion molecule, fractalkine induces vascular dysfunction by stimulating vascular reactive oxygen species resulting in reduced NO bioavailability.

Flow velocities after carotid artery stenting: impact of stent design. A fluid dynamics study in a carotid artery model with laser Doppler anemometry.

Purpose To study the influence of a newly developed membrane stent design on flow patterns in a physiologic carotid artery model.MethodsThree different stents were positioned in silicone models of the carotid artery: a stainless steel stent (Wall-stent), a nitinol stent (SelfX), and a nitinol stent with a semipermeable membrane (MembraX). To increase the contact area of the membrane with the vessel wall, another MembranX model was modified at the outflow tract. The membrane consists of a biocompatible silicone-polyurethane copolymer (Elast-Eon) with a pore size of 100 μm. All stents were deployed across the bifurcation and the external carotid artery origin. Flow velocity measurements were performed with laser Doppler anemometry (LDA), using pulsatile flow conditions (Re = 220; flow 0.39 l/min; flow rate ratio ICA:ECA = 70:30) in hemodynamically relevant cross-sections. The hemodynamic changes were analyzed by comparing velocity fluctuations of corresponding flow profiles.ResultsThe flow rate ratio ICA:ECA shifted significantly from 70/30 to 73.9/26.1 in the MembraX and remained nearly unchanged in the SelfX and Wallstent. There were no changes in the flow patterns at the inflow proximal to the stents. In the stent no relevant changes were found in the SelfX. In the Wallstent the separation zone shifted from the orifice of the ICA to the distal end of the stent. Four millimeters distal to the SelfX and the Wallstent the flow profile returned to normal. In the MembraX an increase in the central slipstreams was found with creation of a flow separation distal to the stent. With a modification of the membrane this flow separation vanished. In the ECA flow disturbances were seen at the inner wall distal to the stent struts in the SelfX and the Wallstent. With the MembraX a calming of flow could be observed in the ECA with a slight loss of flow volume.ConclusionsStent placement across the carotid artery bifurcation induces alterations of the physiologic flow behavior. Depending on the stent design the flow alterations are located in different regions. All the stents tested were suitable for the carotid bifurcation. The MembraX prototype has shown promising hemodynamic properties ex vivo.

Evaluation of Serum Matrix Metalloproteinases as Biomarkers for Detection of Neurological Symptoms in Carotid Artery Disease

Objective: Relevant soluble matrix metalloproteinases (MMPs), their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), and serological factors were analyzed as possible biomarkers for neurological symptoms in patients with carotid artery stenosis. Methods and Results: Asymptomatic (n = 76) and symptomatic (n = 69) patients were evaluated. Serum levels of collagenases (MMP-1, -8), gelatinases (MMP-2, -9), stromelysin (MMP-3), matrilysin (MMP-7), and TIMP-1, -2 were determined by enzyme-linked immunosorbant assay (ELISA). Furthermore, fibrinogen, C-reactive protein (CRP), leukocytes, and further serological parameters were measured. Circulating MMP-7, -8, -9, and TIMP-1 were significantly enhanced in symptomatic individuals with P < .001 for MMP-7 and P < .05 for MMP-8, -9, and TIMP-1. Significant correlations were found between various MMPs with highest correlation coefficient of r = .749 between MMP-8 and -9. In addition, MMP-1, -3, -7, -9 correlated significantly with leukocytes, MMP-1, and TIMP-1 with thrombocytes, MMP-8 with fibrinogen, and MMP-7 with creatinine. Combination of more than one bio-marker led to significantly enhanced positive predictive value (PPV) for neurological symptom compared to single MMP (MMP-7 + MMP-9: PPV = 73.1%, MMP-7 + MMP-8 + MMP-9: PPV = 73.8% vs. PPV = 62.5%; P < .001). Conclusions: Thus, using appropriate analytical approaches, we showed for the first time the possibility to use set of relevant biomarkers as predictors of neurological symptoms. Such biomarkers together with current diagnostic techniques may further contribute to recognize vulnerable lesions to define patients at risk.