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Background: Carotid plaque neovascularization (vasa vasorum [VV]) may be useful for detecting high-risk atherosclerotic plaques. Contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are 2 commonly used techniques for imaging VV of the carotid plaque, yet the relationship between their measurements remains unknown. Objectives: We aimed to blindly evaluate the correlation between CEUS and DCE-MRI in measuring carotid plaque VV. Methods: We recruited subjects with asymptomatic carotid stenosis (≥50%). VV was graded by CEUS, based on richness of contrast signal, according to 3 different methods named CEUS_A, CEUS_B and CEUS_C on different point scales (the higher the values, the higher the estimated VV). A 3.0 T MRI scanner was used for VV quantification by DCE-MRI using gadolinium contrast kinetic modelling for computing the fractional plasma volume (vp) and transfer constant (Ktrans). Results: The analysis included 30 patients. A significant correlation between CEUS and DCE-MRI findings was observed when CEUS_C was used for neovessel grading and DCE-MRI was used to determine adventitial (r = 0.460, p = 0.010) and plaque (r = 0.374, p = 0.042) Ktrans values. CEUS_B (r = 0.416, p = 0.022) and CEUS_C (r = 0.443, p = 0.014) grading showed a significant correlation with regard to the maximal Ktrans. Conclusions: We found a positive but weak correlation and a moderate diagnostic agreement between neovessels as visually graded by CEUS and adventitial neovessels assessed by DCE-MRI Ktrans in carotid atherosclerosis. These findings may help in understanding how VV density, flow, and permeability influence in vivo measurements by CEUS and DCE-MRI as well as in selecting the most appropriate variables and imaging method in future research and potentially in clinical settings. Further confirmative studies are necessary to confirm our results.

Supplementary Material to this article is available at www.thrombosis-online.com.

In the last years, the concepts of plaque vulnerability, composition of the plaque, and ­cerebrovascular events have been vastly studied. The gray scale median (GSM) score has been proposed with the intent of identifying asymptomatic patients at high risk of stroke. Several studies demonstrated the relationship between carotid plaque echolucency ­evaluated by GSM, hs-CRP, carotid plaque infiltration by macrophage, neovascularization, plaque rupture, embolic load to the brain, and eventually risk of stroke. The GSM analysis has been included in the current guidelines for treatment of patients with carotid stenoses, both with endovascular and surgical approach.

Heme oxygenase-1 (HO-1, encoded by the HMOX1 gene) and inducible nitric oxide synthase (iNOS) have been implicated in vascular disease; however the role of these genes remains unclear. Therefore, we studied the mechanism by which iNOS-derived nitric oxide (NO) affects the intimal hyperplasia (IH) formation in relation to HO-1. We show, in a model of balloon injury in rats, that the suppression of vascular smooth muscle cells (VSMC) proliferation by NO required HO-1, while induction of apoptosis of the VSMC by NO does not involve HO-1. To better clarify the molecular mechanism of this finding, we used Hmox1+/+ and Hmox1-/- VSMC exposed to NO. In Hmox1+/+ VSMC, NO is antiproliferative (up to 34% inhibition) and it is associated to an increase of apoptosis (up to 35%) due to a decrease of X-linked inhibitor of apoptosis protein (XIAP) expression level and to the activation of caspase-3. In the absence of HO-1 (Hmox1-/- VSMC) apoptosis was significantly greater (69% p

Objective Most strategies against intimal hyperplasia developed in several preclinical models failed in terms of clinical application, often due to a discrepancy between animal and human disease. The aim of this study was to setup for the first time a porcine vascular injury model with mild hypercholesterolemia able to significantly increase the degree of stenosis resembling human settings and investigate the pathogenetic role of hypercholesterolemia on protective genes and inflammatory response affecting matrix deposition and cell proliferation. Methods Pigs were fed with standard (SD, n = 7) or high-cholesterol diet (HCD, n = 7) for 120 days. A balloon angioplasty injury was induced in carotid arteries. Results Hypercholesterolemia induced a mild significant increase of total and LDL cholesterolemia. HCD significantly increased the degree of stenosis (48 ± 3% vs. 13 ± 4%, p = 0.001), with induction of cell proliferation, matrix deposition, TGF-β1/TGFβRII and MMP2 expression and reduction of collagen. The reduced expression of the protective gene heme oxygenase-1 and inducible-nitric oxide synthase in HCD was associated to a systemic inflammation with a significant increase in circulating leukocytes, serum IFN-γ and TNF-α and a local inflammatory response with an increase of CD3-positive cell infiltrates. There was a significant correlation between CD3 infiltrates and the degree of stenosis. Conclusion We developed for the first time a porcine vascular injury model with mild hypercholesterolemia able to significantly increase the degree of stenosis and showed the pathogenetic role of hypercholesterolemia on intimal hyperplasia. New therapeutical strategies to prevent restenosis can be tested in this preclinical hypercholesterolemic model resembling human disease.

Stenting of carotid artery disease has emerged as a potential alternative to carotid endarterectomy (CEA), the current gold standard treatment for carotid artery lesions.1, 2, 3, 4 After the initial experience with an unacceptably high rate of neurologic complications, the results have now improved, and, as a consequence, several trials have been planned to compare carotid angioplasty/stenting (CAS) with CEA.5

To the Editor: Dr Reiter analyzed the relationship between carotid plaque morphology and the risk of stroke after carotid artery stenting (CAS), showing that the grayscale median (GSM) is not associated with adverse outcome.1 In the ICAROS Study, we demonstrated that GSM is a predictor of stroke during CAS.2 Dr Cremonesi, with one of the biggest CAS experiences, has already demonstrated Dr Reiter’s findings. They treated patients with a GSM

The effectiveness of carotid endarterectomy (CEA) in the prevention of stroke in symptomatic and asymptomatic patients with carotid stenosis has been demonstrated by several randomized studies (Ferguson et al. 1999; Halliday et al. 2004; MRC European Carotid Surgery Trial 1991; ECACAS 1995). Carotid artery stenting (CAS) is an alternative technique that gives favorable results when associated with the use of brain protection devices (BPD) (Cremonesi et al. 2003).

Stroke is the third leading cause of death and the first cause of disability, which burdens society with the need to supply extensive resources for assistance and rehabilitation. The prevention of stroke has consequently become of utmost importance in modern healthcare. Years ago, several randomized controlled trials (RCT) demonstrated the efficacy of carotid endarterectomy (CEA) in the prevention of stroke in patients with carotid atherosclerosis. 1–4 However, the subsequent introduction of carotid artery stenting (CAS) stressed the need for a critical revision to the management strategy for patients with carotid plaques. One issue that deserves the highest consideration is the indication for treatment. In this article, we analyzed the conventional and emerging parameters used to select surgical or endovascular treatment of carotid artery stenoses, namely, the therapeutic options, risk factors influencing outcome, and evidence supporting various management approaches for patients with carotid disease.

The Registro Italiano per lo Stenting Carotideo (RISC, Italian Registry for Carotid Stenting) has been organized by Italian specialists from different disciplines directly involved in the prevention of stroke due to carotid plaques through stenting of carotid lesions. The Registry has been endorsed by the national societies of 4 different specialties: vascular surgery, interventional cardiology, radiology, and neuroradiology. Each society contributed in the planning stage. The basis for the registry is to collect data on carotid stenting procedures performed by different specialists with different techniques in a "real-world" setting without the limitations of a randomized clinical trial. The Registry was funded to enroll at least 1200 patients over a minimum period of 36 months. The results will be analyzed using the intention-to-treat principle and are anticipated in late 2006. Primary endpoints of the registry are the 30-day combined death and stroke rate and the occurrence of restenosis and ipsilateral neurological deficit at 12 and 24 months. Considerable attention has been paid to the registry's quality control program to ensure scientific validation. An online database facilitates the collection of data with speed and accuracy.

Background— Bilirubin, a natural product of heme catabolism by heme oxygenases, was considered a toxic waste product until 1987, when its antioxidant potential was recognized. On the basis of observations that oxidative stress is a potent trigger in vascular proliferative responses, that heme oxygenase-1 is antiatherogenic, and that several studies now show that individuals with high-normal or supranormal levels of plasma bilirubin have a lesser incidence of atherosclerosis-related diseases, we hypothesized that bilirubin would have salutary effects on preventing intimal hyperplasia after balloon injury. Methods and Results— We found less balloon injury–induced neointima formation in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor of bilirubin, than in controls. In vitro, bilirubin and biliverdin inhibited serum-driven smooth muscle cell cycle progression at the G 1 phase via inhibition of the mitogen-activated protein kinase signal transduction pathways and inhibition of phosphorylation of the retinoblastoma tumor suppressor protein. Conclusions— Bilirubin and biliverdin might be potential therapeutics in vascular proliferative disorders.

Background— Carotid artery stenting (CAS) has recently emerged as a potential alternative to carotid endarterectomy. Cerebral embolization is the most devastating complication of CAS, and the echogenicity of carotid plaque has been indicated as one of the risk factors involved. This is the first study to analyze the role of a computer-assisted highly reproducible index of echogenicity, namely the gray-scale median (GSM), on the risk of stroke during CAS. Methods and Results— The Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) registry included 418 cases of CAS collected from 11 international centers. An echographic evaluation of carotid plaque with GSM measurement was made preprocedurally. The onset of neurological deficits during the procedure and the postprocedural period was recorded. The overall rate of neurological complications was 3.6%: minor strokes, 2.2%, and major stroke, 1.4%. There were 11 of 155 strokes (7.1%) in patients with GSM ≤25 and 4 of 263 (1.5%) in patients with GSM >25 ( P =0.005). Patients with severe stenosis (≥85%) had a higher rate of stroke ( P =0.03). The effectiveness of brain protection devices was confirmed in those with GSM >25 ( P =0.01) but not in those with GSM ≤25. Multivariate analysis revealed that GSM (OR, 7.11; P =0.002) and rate of stenosis (OR, 5.76; P =0.010) are independent predictors of stroke. Conclusions— Carotid plaque echolucency, as measured by GSM ≤25, increases the risk of stroke in CAS. The inclusion of echolucency measured as GSM in the planning of any endovascular procedure of carotid lesions allows stratification of patients at different risks of complications in CAS.

Carotid artery stenting (CAS) is used widely to treat carotid lesions. Indication to CAS is mostly based, both in trial and in clinical practice, on the percentage of stenosis and the presence or absence of preprocedural neurologic symptoms, whereas the features of the plaque are somehow disregarded and ignored. The most severe complication of CAS is stroke, related to cerebral embolization from carotid plaque. Several studies showed that echolucent plaques generate a higher number of embolic particles following carotid stenting. Echolucency can be measured using the gray scale median, which is an objective and quantitative computer-assisted grading of the echogenicity of carotid plaques. As previously demonstrated in the ICAROS study, carotid plaque echolucency is an independent risk factor for stroke in carotid stenting. Carotid plaque echolucency is one of the parameters that should be mandatory to be considered for indication to treatment.