Antoine Millon

Clinical and Histological Significance of Gadolinium Enhancement in Carotid Atherosclerotic Plaque

Background and Purpose— Although the ability of MRI to investigate carotid plaque composition is well established, the mechanism and the significance of plaque gadolinium (Gd) enhancement remain unknown. We evaluated clinical and histological significance of Gd enhancement of carotid plaque in patients undergoing endarterectomy for carotid stenosis. Methods— Sixty-nine patients scheduled for a carotid endarterectomy prospectively underwent a 3-T MRI. Carotid plaque enhancement was assessed on T1-weighted images performed before and 5 minutes after Gd injection. Enhancement was recorded according to its localization. Histological analysis was performed of the entire plaque and of the area with matched contrast enhancement on MR images. Results— Gd enhancement was observed in 59% patients. Three types of carotid plaques were identified depending on enhancement location (shoulder region, shoulder and fibrous cap, and central in the plaque). Fibrous cap rupture, intraplaque hemorrhage, and plaque Gd enhancement was significantly more frequent in symptomatic than in asymptomatic patients (P=0.043, P<0.0001, and P=0.034, respectively). After histological analysis, Gd enhancement was significantly associated with vulnerable plaque (American Heart Association VI, P=0.006), neovascularization (P<0.0001), macrophages (P=0.030), and loose fibrosis (P<0.0001). Prevalence of neovessels, macrophages, and loose fibrosis in the area of Gd enhancement was 97%, 87%, and 80%, respectively, and was different depending on the enhancement location in the plaque. Fibrous cap status and composition were different depending on the type of plaque. Conclusions— Gd enhancement of carotid plaque is associated with vulnerable plaque phenotypes and related to an inflammatory process.

Molecular Imaging in Atherosclerosis: FDG PET

Abstract18F-FDG PET is a new noninvasive tool for inflammation functional imaging. Low spatial resolution is now compensated by coregistration with CT or MRI. New mechanistic insights have emerged from animal and histology to explain the obtained signals by hypoxia, macrophage infiltration, and differentiation. Mixed results have been found in biomarkers studies. Interesting data have come recently linking plaque anatomy and function in carotids and in aortic aneurysms as well as inflammation and events. In coronary arteries, plaque assessment is still hampered by myocardium uptake but developments are being made. 18-FDG PET has been able to monitor inflammation before and after several therapies in animals and humans but to date the lack of standardization and the absence of prospective event-driven studies prevent this promising technique to be used in clinical practice.

High-resolution magnetic resonance imaging of carotid atherosclerosis identifies vulnerable carotid plaques

OBJECTIVE Carotid magnetic resonance imaging (MRI) may be a useful tool in characterizing carotid plaque vulnerability, but large studies are still lacking. The purpose of this study was to assess carotid MRI features of vulnerable plaque in a large study and the changes in carotid plaque morphology with respect to time since the neurological event. METHODS We included 161 patients with carotid plaque more than 3 mm thick. All patients underwent carotid MRI to obtain 3-T high-resolution magnetic resonance sequences. Large lipid core, intraplaque hemorrhage (IPH), fibrous cap rupture (FCR), and gadolinium enhancement (GE) were assessed and classified as present or absent. Prevalences of these features were then compared between symptomatic and asymptomatic patients and time since stroke. RESULTS Seven patients were excluded because of poor image quality. Of the remaining 154 patients, 52 were symptomatic and 102 were asymptomatic. The prevalences of IPH (39 vs 16%; P = .002), FCR (30 vs 9%; P = .001), and GE (75 vs 55%; P = .015) were significantly higher in symptomatic than asymptomatic patients. After multivariate analysis, the prevalences of IPH (odds ratio, 2.6; P = .023) and FCR (odds ratio, 2.8; P = .038) were still significantly higher. The prevalence of IPH was significantly higher in symptomatic patients with plaque regardless of the time since the neurological event. For FCR, the difference between symptomatic and asymptomatic patients was significant only during the first 15 days after the neurological event. CONCLUSIONS Carotid MRI can identify plaque features that are associated with symptomatic presentation and may be indicative of plaque vulnerability. These features may ultimately be used in the management of extracranial carotid stenosis.

Conversion to open repair after endovascular aneurysm repair: causes and results. A French multicentric study.

OBJECTIVE To evaluate the causes and results of conversion to open repair after aortic aneurysm endovascular treatment (EVAR). DESIGN Retrospective study of open conversion after EVAR was performed in eight French academic centres. Primary conversion (PC) within 30 days after EVAR and secondary conversions (SC) were analysed separately. RESULT Between 1997 and 2007, open conversions were performed in 34 patients (most often in high-risk patients): 14 PC and 20 SC. Two main causes of PC were unfavourable iliac artery anatomy and renal artery coverage. In hospital mortality was 21%. SC occurred at a median of 44 months after primary EVAR. Nine were urgent cases for rupture or infection and 11 elective for aneurysm growth, infection or thrombosis. Early mortality was similar after emergent or elective SC (25%). CONCLUSION Open conversion, and, in particular, PC and urgent SC, was associated with a poor outcome. According to the literature, mortality after elective SC is low but remains high in high-risk patients.

Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling

Background —Alternatively Spliced Tissue Factor (asTF) is a novel isoform of full-length Tissue Factor (fl-TF) that exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype. Methods and Results —Carotid (n=10) and coronary specimens (n=8), from patients with stable or unstable angina, were classified as complicated or uncomplicated based on plaque morphology. Analysis of asTF expression and cell type -specific expression revealed a strong expression and co-localization of asTF with macrophages and neovessels within complicated, but not un-complicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via HIF-1α up-regulation through integrins and activation of phosphatidylinositol-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways. HIF-1α up-regulation by asTF also was associated with increased VEGF expression in primary human endothelial cells, and VEGF-Trap significantly reduced the angiogenic effect of asTF in vivo . Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization following carotid wire injury in ApoE-/- mice. Conclusions —The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Herein, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the HIF-1/VEGF signaling. This mechanism may be relevant to neovascularization, progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated vs. uncomplicated human carotid and coronary plaques.Background— Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype. Methods and Results— Carotid (n=10) and coronary (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology. Analysis of asTF expression and cell type–specific expression revealed a strong expression and colocalization of asTF with macrophages and neovessels within complicated, but not uncomplicated, human plaques. Our results showed that the angiogenic activity of asTF is mediated via hypoxia-inducible factor-1&agr; upregulation through integrins and activation of phosphatidylinositol-3-kinase/Akt and mitogen-activated protein kinase pathways. Hypoxia-inducible factor-1&agr; upregulation by asTF also was associated with increased vascular endothelial growth factor expression in primary human endothelial cells, and vascular endothelial growth factor–Trap significantly reduced the angiogenic effect of asTF in vivo. Furthermore, asTF gene transfer significantly increased neointima formation and neovascularization after carotid wire injury in ApoE−/− mice. Conclusions— The results of this study provide strong evidence that asTF promotes neointima formation and angiogenesis in an experimental model of accelerated atherosclerosis. Here, we demonstrate that the angiogenic effect of asTF is mediated via the activation of the hypoxia-inducible factor-1/vascular endothelial growth factor signaling. This mechanism may be relevant to neovascularization and the progression and associated complications of human atherosclerosis as suggested by the increased expression of asTF in complicated versus uncomplicated human carotid and coronary plaques.

Three-dimensional dynamic contrast-enhanced MRI for the accurate, extensive quantification of microvascular permeability in atherosclerotic plaques.

Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast‐enhanced MRI (DCE‐MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE‐MRI studies of atherosclerosis have been limited to two‐dimensional (2D) multi‐slice imaging. Although providing the high spatial resolution required to image the arterial vessel wall, these approaches do not allow the quantification of plaque permeability with extensive anatomical coverage, an essential feature when imaging heterogeneous diseases, such as atherosclerosis. To our knowledge, we present the first systematic evaluation of three‐dimensional (3D), high‐resolution, DCE‐MRI for the extensive quantification of plaque permeability along an entire vascular bed, with validation in atherosclerotic rabbits. We compare two acquisitions: 3D turbo field echo (TFE) with motion‐sensitized‐driven equilibrium (MSDE) preparation and 3D turbo spin echo (TSE). We find 3D TFE DCE‐MRI to be superior to 3D TSE DCE‐MRI in terms of temporal stability metrics. Both sequences show good intra‐ and inter‐observer reliability, and significant correlation with ex vivo permeability measurements by Evans Blue near‐infrared fluorescence (NIRF). In addition, we explore the feasibility of using compressed sensing to accelerate 3D DCE‐MRI of atherosclerosis, to improve its temporal resolution and therefore the accuracy of permeability quantification. Using retrospective under‐sampling and reconstructions, we show that compressed sensing alone may allow the acceleration of 3D DCE‐MRI by up to four‐fold. We anticipate that the development of high‐spatial‐resolution 3D DCE‐MRI with prospective compressed sensing acceleration may allow for the more accurate and extensive quantification of atherosclerotic plaque permeability along an entire vascular bed. We foresee that this approach may allow for the comprehensive and accurate evaluation of plaque permeability in patients, and may be a useful tool to assess the therapeutic response to approved and novel drugs for cardiovascular disease. Copyright

Animal models of atherosclerosis and magnetic resonance imaging for monitoring plaque progression

Atherosclerosis, the main cause of heart attack and stroke, is the leading cause of death in most modern countries. Preventing clinical events depends on a better understanding of the mechanism of atherosclerotic plaque destabilization. Our knowledge on the characteristics of vulnerable plaques in humans has grown past decades. Histological studies have provided a precise definition of high-risk lesions and novel imaging methods for human atherosclerotic plaque characterization have made significant progress. However the pathological mechanisms leading from stable lesions to the formation of vulnerable plaques remain uncertain and the related clinical events are unpredictable. An animal model mimicking human plaque destablization is required as well as an in vivo imaging method to assess and monitor atherosclerosis progression. Magnetic resonance imaging (MRI) is increasingly used for in vivo assessment of atherosclerotic plaques in the human carotids. MRI provides well-characterized morphological and functional features of human atherosclerotic plaque which can be also assessed in animal models. This review summarizes the most common species used as animal models for experimental atherosclerosis, the techniques to induce atherosclerosis and to obtain vulnerable plaques, together with the role of MRI for monitoring atherosclerotic plaques in animals.

Midterm Outcomes of Embolisation of Internal Iliac Artery Aneurysms

OBJECTIVES There is no standardised technique for internal iliac artery aneurysm (IIAA) embolisation and results of long-term prevention of rupture are unknown. DESIGN We retrospectively evaluated technical aspects and results of IIAA embolisation in a multicentre study. METHODS Aneurysm morphology and embolisation techniques were reviewed. Aneurysm-related death, rupture, diameter increase, endoleak, secondary procedure and complication related to the IIA occlusion were recorded. RESULTS Between 2001 and 2011, 53 patients with 57 IIAA were treated. Mean diameter of IIAA was 41 mm (range: 25-88 mm). Embolisation techniques were distal and proximal occlusion (n = 24), proximal occlusion (n = 18) and sac packing (n = 15). Cumulative overall survival rate was 92% at 1 year, 83% at 3 years and 59% at 5 years. No cause of deaths was related to aneurysm. Aneurysm diameter increased in five patients and endoleak was observed in 11 patients. One secondary open conversion and five secondary endovascular procedures were performed for increase of diameter or proximal endoleak. Two patients experienced a disabling buttock claudication. CONCLUSIONS Embolisation of IIAA is safe in the short- and midterm. However, endoleak and aneurysm diameter increases are not rare. Yearly post-procedure computed tomography angiography seems appropriate.

The Antegrade Approach Using Transbrachial Access Improves Technical Success Rate of Endovascular Recanalization of TASC C-D Aortoiliac Occlusion in Case of Failed Femoral Access

BACKGROUND Technical success rates of endovascular recanalizations for Trans-Atlantic Inter-Society Consensus (TASC) C-D chronic occlusions are highly variable and depend on the characteristics and sites of the lesions as well as on the operator experience. We hypothesized that an antegrade approach via transbrachial access could improve the technical success rate of endovascular treatment of TASC C-D occlusions in case of failed femoral access. METHODS From January 2010 to December 2012, all patients with symptomatic chronic TASC C-D aortoiliac occlusion were treated with an endovascular-first approach. Recanalization was first attempted using a femoral access. In case of failure, an antegrade approach using a transbrachial access was performed. Patient characteristics, anatomic details, procedural data, and immediate outcomes were prospectively recorded. RESULTS During the study period, 73 patients (99 arteries) were included. Twenty-seven (37%) patients had TASC C occlusions including 11 bilateral common iliac artery occlusions and 16 external iliac artery (EIA) occlusions involving the common femoral or the internal iliac arteries. Forty-six (63%) patients had TASC D occlusions including 10 aortoiliac occlusions, 31 unilateral occlusions of both common and EIAs, and 5 bilateral EIA occlusions. Technical success with femoral access has been obtained in 53 arteries. An antegrade approach via transbrachial access allowed technical success in the other arteries, except in 7 arteries. Overall technical success rate was 93%, and 2 complications were related to the brachial accesses including 1 thrombosis and 1 pseudoaneurysm both requiring a reintervention. CONCLUSIONS Brachial access for TASC C-D aortoiliac chronic occlusion improves the technical success rate without the need for reentry devices.

Carotid plaque high-resolution MRI at 3 T: evaluation of a new imaging score for symptomatic plaque assessment

PURPOSE To assess the sensitivity and specificity of intra-plaque hemorrhage (IPH), large lipid-rich necrotic core (LR-NC) and ulceration or cap rupture (UCR) for symptomatic carotid plaque characterization and to evaluate a new imaging score [Hemorrhage, Ulceration or cap rupture, Lipid-rich necrotic Core (HULC) score based on the sum of presence/absence of IPH, UCR and LR-NC; range 0-3] for assessment of recently symptomatic carotid plaques. MATERIAL AND METHODS Twenty-seven recently symptomatic (<8 weeks) and 36 asymptomatic patients with a carotid plaque thicker than 2 mm were prospectively imaged on a 3-T magnetic resonance (MR) system using high-resolution, multi-contrast MR sequences. Prior to analysis, all images were reviewed to assess image quality of each sequence. Sensitivity and specificity of IPH, LR-NC, UCR and HULC scores were calculated. RESULTS Fifty-one patients were analyzed (26 symptomatic carotids and 67 asymptomatic carotids) after exclusion of studies with poor image quality. Sensitivity and specificity for symptomatic carotid plaque was, respectively, 46.1% and 97% for IPH, 84.6% and 73.1% for UCR and 80.7% and 76.1% for LR-NC. A HULC score of 2 or more showed a sensitivity of 73% and a specificity of 92.5%. CONCLUSION At 3 T, intra-plaque hemorrhage is the most specific criterion to characterize symptomatic carotid plaque. The HULC score offers the best compromise between sensitivity and specificity.