The prospective GermanVasc cohort study.

Background: Previous observational studies reported a wide variation and possible room for improvement in the treatment of patients suffering from symptomatic peripheral artery disease (PAD). Yet, systematic assessment of everyday clinical practice is lacking. A General Data Protection Regulation (GDPR) compliant registry was developed and used to collect comprehensive data on clinical treatment and outcomes regarding PAD in Germany. Here, we report baseline characteristics of patients prospectively enrolled until the end of 2020. Methods: The GermanVasc registry study is a prospective longitudinal multicentre cohort study. Between 1st May 2018 and 31st December 2020, invasive endovascular, open-surgical, and hybrid revascularisations of patients suffering from chronic symptomatic PAD were prospectively included after explicit informed consent (NCT03098290). For ensuring high quality of the data, we performed comprehensive risk-based and random-sample external and internal validation. Results: In total, 5608 patients from 31 study centres were included (34% females, median 69 years). On-site monitoring visits were performed at least once in all centres. The proportion of chronic limb-threatening ischaemia was 30% and 13% were emergent admissions. 55% exhibited a previous revascularisation. Endovascular techniques made 69% among all documented invasive procedures (n=6449). Thirty-five percent were classified as patients with severe systemic disease, and 3% exhibited a constant threat to life according to the American Society of Anaesthesiologists classification. The risk profile comprised of 75% former or current smokers, 36% diabetes mellitus, and in 30% a current ischemic heart disease was present. At discharge, 93% of the patients received antiplatelets and 77% received statins. Conclusions: The GermanVasc registry study provides insights into real-world practice of treatment and outcomes of 5,608 patients with symptomatic PAD in Germany. The cohort covers a broader range of disease severity and types of interventions than usually found in trials. In future studies, comparative outcomes will be analysed in more detail.

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 value of the serum neurofilament protein heavy chain as a biomarker for peri-operative brain injury after carotid endarterectomy.

This prospective study examined the value of serum neurofilament protein levels for detecting peri-operative brain damage following carotid endarterectomy. An ELISA was used for quantification of neurofilament protein heavy chain (NfH(SMI35)) levels from patients undergoing endarterectomy for symptomatic (n = 17) and asymptomatic high-grade internal carotid artery stenosis (n = 30). All patients underwent diffusion-weighted brain imaging before and after the procedure. NfH(SMI35) levels were significantly higher in patients with a symptomatic carotid artery stenosis (0.131 ng/ml) if compared to asymptomatic patients (0.055 ng/ml, P = 0.01). However, serum NfH(SMI35) levels were not related to signs of brain ischemia on routine brain imaging techniques. Our pilot data suggests that raised NfH(SMI35) serum levels in patients with symptomatic carotid artery disease may be a sensitive biomarker for diffuse ischemic damage to the CNS. We conclude that NfH(SMI35) failed to qualify as a biomarker for peri-operative brain injury in CEA and factors that may have compromised the validation of this biomarker are discussed and need to be taken into account for the design of further studies.

Improvement of microcirculation after percutaneous transluminal angioplasty in the lower limb with prostaglandin E1.

OBJECTIVE: The aim of the study was to investigate prospectively the microcirculation after angioplasty and its improvement with additional Prostaglandin E1 (PGE1) therapy assessed by transcutaneous pressure of oxygen. PATIENTS AND METHODS: 45 patients with intermittent claudication eligible for angioplasty were enrolled in a prospective randomised controlled clinical trial. Patients received either intra-arterial bolus of 40 microg PGE1 in addition to angioplasty or a 40 microg PGE1 intravenous infusion. Control group received no trial medication. Additional 15 patients undergoing intra-arterial angiography were also investigated. tcpO(2) values were recorded distal to the PTA region before, during the intervention, 24h, 2 and 4 weeks after intervention. Clinical endpoint was the change of tcpO(2) values 4 weeks after intervention. RESULTS: During the 4 week follow-up tcpO(2) values decreased in patients treated with angioplasty. At the same time tcpO(2) increased significantly in those patients additionally treated with intra-arterial PGE1 bolus injection as well as with intravenous PGE1 infusion. CONCLUSIONS: Impaired microcirculation after angioplasty can be improved with additional intravenous as well as intra-arterial PGE1 administration.

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 microg/mL) did not directly induce contractile or relaxant responses when applied to rat aortic rings in organ baths. Short-term incubation with fractalkine (1 microg/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. CONCLUSIONS: 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.

Lack of association between right-to-left shunt and cerebral ischemia after adjustment for gender and age.

INTRODUCTION: A number of studies has addressed the possible association between patent foramen ovale (PFO) and stroke. However, the role of PFO in the pathogenesis of cerebral ischemia has remained controversial and most studies did not analyze patient subgroups stratified for gender, age and origin of stroke. METHODS: To address the role of PFO for the occurrence of cerebral ischemia, we investigated the prevalence of right-to-left shunt in a large group of patients with acute stroke or TIA. 763 consecutive patients admitted to our hospital with cerebral ischemia were analyzed. All patients were screened for the presence of PFO by contrast-enhanced transcranial Doppler sonography at rest and during Valsalva maneuver. Subgroup analyses were performed in patients stratified for gender, age and origin of stroke. RESULTS: A right-to-left shunt was detected in 140 (28%) male and in 114 (42%) female patients during Valsalva maneuver, and in 66 (13%) and 44 (16%) at rest respectively. Patients with right-to-left shunt were younger than those without (P < 0.001). PFO was associated with stroke of unknown origin in male (P = 0.001) but not female patients (P > 0.05). After adjusting for age no significant association between PFO and stroke of unknown origin was found in either group. CONCLUSION: Our findings argue against paradoxical embolization as a major cause of cerebral ischemia in patients with right-to-left shunt. Our data demonstrate substantial gender-and age-related differences that should be taken into account in future studies.

Transcutaneous oximetry compared to ankle-brachial-index measurement in the evaluation of percutaneous transluminal angioplasty.

OBJECTIVE: To investigate transcutaneous oximetry as parameter of the microcirculation is correlated to ankle-brachial-index as parameter of the macrocirculation after peripheral angioplasty procedures. DESIGN: Prospective study. MATERIALS AND METHODS: 60 patients suffering from intermittent claudication were scheduled for angioplasty treatment. 45 patients were considered as eligible for angioplasty after angiographic evaluation, 15 patients underwent angiography only. Transcutaneous oximetry measurements were performed before the procedure, at the end of intervention, 24h as well as 2 and 4 weeks after percutaneous transluminal angioplasty. Ankle-brachial-indices were obtained before intervention, 24h as well as 2 and 4 weeks later. RESULTS: Ankle-brachial-indices increased significantly at 24h after angioplasty in patients being treated with angioplasty. Transcutaneous oximetry values dropped significantly at the end of the procedure and returned close to the baseline levels at 2 and 4 weeks after angioplasty. Ankle-brachial-indices and transcutaneous oximetry were positively correlated before (r=0.3833, p=0.009) as well as 4 weeks after angioplasty (r=0.4596, p=0.001). Immediately after radiological interventions, ankle-brachial-indices and transcutaneous oximetry are not positively correlated. In patients undergoing angiography only, transcutaneous oximetry levels drop significantly immediately after angiography and remain at decreased levels even at 4 weeks after intervention. CONCLUSION: Transcutaneous oximetry as parameter of the microcirculation is positively correlated with ankle-brachial-index as parameter of the macrocirculation before and at 4 weeks after angioplasty. Intraarterial angiography leads to a sudden decrease in skin microcirculation without affecting macrocirculation. As indicated by a lack of recovery in transcutaneous oximetry levels after 4 weeks, angiography alone results in a prolonged impaired microcirculation which may reflect endothelial dysfunction caused by contrast material. The recovery of transcutaneous oximetry levels following angioplasty is counterbalanced by the adverse effects of the contrast material. Ankle-brachial-indices remains the most favourable parameter in evaluating the success of angioplasty procedures while transcutaneous oximetry serves as an indirect method in assessing endothelial dysfunction caused by contrast material.

Ex vivo characterization of carotid plaques by intravascular ultrasonography and virtual histology: concordance with real plaque pathomorphology.

BACKGROUND: The purpose of this study was to evaluate the accuracy of carotid plaque characterisation by virtual histology using intravascular ultrasonography (VH-IVUS) by comparing the results with real morphology. METHODS: Following elective carotid endarterectomy (CEA), atherosclerotic plaques from 36 patients (19 asymptomatic, 17 symptomatic) underwent ex-vivo VH-IVUS examination. Afterwards, tissue specimens were fixed with formalin and embedded in paraffin. Atherosclerotic lesions were characterised following hematoxylin/eosin (HE) and Elastin van Gieson (EvG) staining using AHA classification (stages I to VIII). The plaque composition, cellularity, severity of inflammation, and atheroma-associated macrophages and foam cells were compared with virtual histology. RESULTS: Patients with symptomatic carotid artery stenosis showed most commonly lesion type IV-V (N.=9; 52.9%), followed by type VI (N.=3; 17.6%) and type VII (N.=3, 17.6%), type VIII (N.=1; 5.9%) and type I-III (N.=1; 5.9%). In asymptomatic patients with the main lesion was type VII (N.=8; 42.1%), followed by type I-III (N.=4; 21.1%), type IV-V (N.=3, 15.8%) and type VIII (N.=1; 5.3%). The composition of unstable lesions differed significantly in symptomatic patients compared to asymptomatic subjects (70.1% vs. 31.6%, P=0.03). The concordance between the histological results and the VH-IVUS classification was 86.1% (Cohen`s kappa of 0.72). CONCLUSIONS: In the present study, our findings demonstrated significant correlation between true plaque composition determined by histology and VH-IVUS. Thus, IVUS might be useful as an additional diagnostic method to detect patients with unstable rupture-prone plaques.

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. CONCLUSIONS: MES could be regularly detected during CEA. Dissection and shunting seem to be the most vulnerable stages of the procedure.

Synthesis and use of alpha-silyl-substituted alpha-hydroxyacetic acids.

[reaction: see text] Rhodium-catalyzed oxygen transfer was used to generate benzyl 2-silyl-2-oxoacetates in good yields. The hydrogenation of these compounds led to chiral alpha-silyl-substituted alpha-hydroxyacetic acids. Resolution by means of HPLC using a chiral stationary phase afforded an enantiomerically pure representative of this class of compounds, which was successfully applied as a chiral ligand in an asymmetric aldol-type reaction.

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

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 0.08 cm(3) in the CEA group and 0.02 cm(3) 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.

PET/CT imaging of integrin αvß3 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 αvß3 expression in human carotid plaques. BACKGROUND: The integrin αvß3 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 αvß3. Therefore, [(18)F]Galacto-RGD PET/CT imaging of αvß3 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 αvß3 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 αvß3-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 αvß3 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 αvß3 expression. Based on these initial data, larger prospective studies are now warranted to evaluate the potential of molecular imaging of αvß3 expression for assessment of plaque inflammation in patients.

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.

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.

Characterization of carotid artery plaques with USPIO-enhanced MRI: assessment of inflammation and vascularity as in vivo imaging biomarkers for plaque vulnerability.

To evaluate ultra small superparamagnetic iron oxide particles (USPIO) enhanced magnetic resonance (MR) imaging for characterization of atherosclerotic carotid plaques by assessing vascularity and plaque inflammation, besides contrast-enhanced MR angiography (CE-MRA) of the carotid artery stenosis. Twelve patients with severe carotid artery stenosis, scheduled for endarterectomy, underwent MRI of the carotid artery bifurcation using SHU 555 C at a dose of 40 µmol Fe/kg BW. The MR imaging protocol comprised pre- and post-contrast T2*-w, a first-pass CE-MRA and dynamic T1-w sequences. For quantitative data analysis, the signal intensities (SI) were measured and SNR-data (SNR = SI(blood/plaque/bone marrow)/standard deviation(noise)) as well as ΔSI-data (SNR(post)-SNR(pre)) were calculated. In addition, two radiologists rated the diagnostic performance of first-pass MRA according to a four level decision scale. Staining of anti-dextran (SHU 555 C) and anti-CD68 (macrophages) was performed for immunohistological confirmation. Plaque sections with a T2*-w signal decline (intracellular USPIO accumulation in macrophages) showed significantly changes (mean -14%, 95% CI, -5 to -20%; P < 0.01) and corresponding plaque regions had significantly higher (15.15 ± 1.76 vs. 5.22 ± 1.50; P < 0.01) T1-w enhancement data (global estimation of vascularity). The first-pass MRA of the supra-aortal vessels provided images of diagnostic quality. Representative immunohistology sections revealed colocalization of dextran- and CD68-immunoreactive cells. USPIO-enhanced MRI is feasible for in vivo assessment of vascularity and macrophage content in atherosclerotic carotid plaques, determining an association of these potential imaging biomarkers of plaque vulnerability. Diagnostic MRA of the supra-aortal vessels can be imaged additionally with a single administration of SHU 555 C.

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 biomarker 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.

Fibrinogen and high-sensitive C-reactive protein as serologic predictors for perioperative cerebral microembolic lesions after carotid endarterectomy.

BACKGROUND: Neurologic deficit caused by cerebral ischemia defines the outcome of carotid endarterectomy (CEA). Although few patients have clinically evident neurologic deficit, diffusion-weighted imaging (DWI) presents a number of cases with ischemic brain lesions. This study should elucidate preoperative risk factors for perioperative microemboli that cause brain infarction. METHODS: We studied 183 patients (58 women, 69.2 +/-12.7 years; 125 men, 69.3 +/- 8.9 years) with high-degree carotid artery stenosis. DWI was performed before and after CEA to analyze new cerebral ischemia. Blood samples were obtained before operation to measure fibrinogen and C-reactive protein (CRP), and preoperative high-sensitive CRP (hsCRP) was analyzed in 30 consecutive patients. RESULTS: Postoperative DWI revealed new ipsilateral ischemic lesions in 41 patients (22.4%), and eight (4.4%) showed new neurologic deficit. Preoperative fibrinogen levels were higher in patients with new lesions (397.6 mg/dL +/- 104.7 mg/dL) than in those without (324.7 mg/dL +/- 74.2 mg/dL, P < .001). Preoperative levels of hsCRP were also higher in patients with new lesions (7.9 mg/dL +/- 5.2 mg/dL) than in those without (2.8 mg/dL +/- 2.6 mg/dL, P = .004). Significant association was found between fibrinogen and CRP (Spearman rho = 0.402; P < .001) as well as hsCRP (Spearman rho = 0.603, P = .003). No association was found between postoperative lesions and CRP (P = .833). CONCLUSION: The present study demonstrates that preoperative levels of fibrinogen and hsCRP are independent determinants for new periprocedural cerebral ischemic lesions caused by microembolic events. There is still not sufficient evidence to recommend measurement of CRP as a prognostic marker for perioperative cerebral lesion.