Pierre Julia

Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial

BACKGROUND Carotid stenting is a potential alternative to carotid endarterectomy but whether this technique is as safe as surgery and whether the long-term protection against stroke is similar to that of surgery are unclear. We previously reported that in patients in the Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, the rate of any stroke or death within 30 days after the procedure was higher with stenting than with endarterectomy. We now report the results up to 4 years. METHODS In this follow-up study of a multicentre, randomised, open, assessor-blinded, non-inferiority trial, we compared outcome after stenting with outcome after endarterectomy in 527 patients who had carotid stenosis of at least 60% that had recently become symptomatic. The primary endpoint of the EVA-3S trial was the rate of any periprocedural stroke or death (ie, within 30 days after the procedure). The prespecified main secondary endpoint was a composite of any periprocedural stroke or death and any non-procedural ipsilateral stroke during up to 4 years of follow-up. Other trial outcomes were any stroke or periprocedural death, any stroke or death, and the above endpoints restricted to disabling or fatal strokes. This trial is registered with ClinicalTrials.gov, number NCT00190398. FINDINGS 262 patients were randomly assigned to endarterectomy and 265 to stenting. The cumulative probability of periprocedural stroke or death and non-procedural ipsilateral stroke after 4 years of follow-up was higher with stenting than with endarterectomy (11.1%vs 6.2%, hazard ratio [HR] 1.97, 95% CI 1.06-3.67; p=0.03). The HR for periprocedural disabling stroke or death and non-procedural fatal or disabling ipsilateral stroke was 2.00 (0.75-5.33; p=0.17). A hazard function analysis showed the 4-year differences in the cumulative probabilities of outcomes between stenting and endarterectomy were largely accounted for by the higher periprocedural (within 30 days of the procedure) risk of stenting compared with endarterectomy. After the periprocedural period, the risk of ipsilateral stroke was low and similar in both treatment groups. For any stroke or periprocedural death, the HR was 1.77 (1.03-3.02; p=0.04). For any stroke or death, the HR was 1.39 (0.96-2.00; p=0.08). INTERPRETATION The results of this study suggest that carotid stenting is as effective as carotid endarterectomy for middle-term prevention of ipsilateral stroke, but the safety of carotid stenting needs to be improved before it can be used as an alternative to carotid endarterectomy in patients with symptomatic carotid stenosis.

Desensitization and Subsequent Kidney Transplantation of Patients Using Intravenous Immunoglobulins (IVIg)

Transplantation of patients possessing antibodies against allo‐HLA antigens can be delayed for years. We have shown that administration of intravenous immunoglobulins (IVIg) can induce a profound and sustained decrease in the titers of anti‐HLA antibodies. We report here the first series of patients desensitized, then transplanted using IVIg therapy. Fifteen patients have been included and treated with IVIg, given as 3 monthly courses of 2 g/kg body weight. Thirteen of those 15 patients (87%) were effectively desensitized and underwent immediate transplantation. Eleven were transplanted with a cadaveric donor, and two with a living donor against which the pretreatment cross‐match was positive. One graft was lost from thrombosis and one from rejection. All other patients had uneventful courses, without any episodes of rejection, with a follow‐up of more than 1 year. Thus, IVIg therapy allows safe and prompt kidney transplantation of immunized patients.

Inhibition of MicroRNA-92a Prevents Endothelial Dysfunction and Atherosclerosis in Mice

Rationale for Study: MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein expression at post-transcriptional level. We hypothesized that a specific pool of endothelial miRNAs could be selectively regulated by flow conditions and inflammatory signals, and as such be involved in the development of atherosclerosis. Objective: To identify miRNAs, called atheromiRs, which are selectively regulated by shear stress and oxidized low-density lipoproteins (oxLDL), and to determine their role in atherogenesis. Methods and Results: Large-scale miRNA profiling in HUVECs identified miR-92a as an atheromiR candidate, whose expression is preferentially upregulated by the combination of low shear stress (SS) and atherogenic oxLDL. Ex vivo analysis of atheroprone and atheroprotected areas of mouse arteries and human atherosclerotic plaques demonstrated the preferential expression of miR-92a in atheroprone low SS regions. In Ldlr−/− mice, miR-92a expression was markedly enhanced by hypercholesterolemia, in particular in atheroprone areas of the aorta. Assessment of endothelial inflammation in gain- and loss-of-function experiments targeting miR-92a expression revealed that miR-92a regulated endothelial cell activation by oxLDL, more specifically under low SS conditions, which was associated with modulation of Kruppel-like factor 2 (KLF2), Kruppel-like factor 4 (KLF4), and suppressor of cytokine signaling 5. miR-92a expression was regulated by signal transducer and activator of transcription 3 in SS- and oxLDL-dependent manner. Furthermore, specific in vivo blockade of miR-92a expression in Ldlr−/− mice reduced endothelial inflammation and altered the development of atherosclerosis, decreasing plaque size and promoting a more stable lesion phenotype. Conclusions: Upregulation of miR-92a by oxLDL in atheroprone areas promotes endothelial activation and the development of atherosclerotic lesions. Therefore, miR-92a antagomir seems as a new atheroprotective therapeutic strategy.

Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia

Critical leg ischemia is associated with a high risk of amputation when revascularization is not possible. Cell therapy based on bone marrow-derived mononuclear cells or with peripheral mononuclear cells, collected after stimulation with G-CSF has been used in an attempt to stimulate angiogenesis. Although several studies have raised the hope that such cell therapy may be effective in critical leg ischemia, no direct demonstration of angiogenesis induced by bone marrow-derived mononuclear cell/peripheral mononuclear cell injection has been reported in man. The aim of this study was to identify and to evaluate the extent of the angiogenic process associated with cell therapy in critical leg ischemia in man. To address this question, this pathological study was conducted in patients enrolled in the OPTIPEC clinical trial (Optimization of Progenitor Endothelial Cells in the Treatment of Critical leg ischemia), an interventional cell therapy study in critical leg ischemia. Amputation specimens from these patients were submitted to a standardized dissection protocol. In three patients, an active angiogenesis was observed in the distal part of the ischemic limb but not in the gastrocnemius muscle, the site of bone marrow cell injection. All the newly formed vessels were positive for endothelial cell markers (CD31, CD34, von Willebrand factor) and negative for markers of lymphatic vessels (podoplanin). Immunohistochemical staining for Ki-67 and c-kit showed extensive endothelial cell proliferation within the new vessels. Bone marrow-derived mononuclear cell therapy in patients with critical leg ischemia induces an active, substained angiogenesis in the ischemic and distal parts of the treated limb, although this may not prevent amputation in some patients with very severe ischemia.

Reduced Immunoregulatory CD31 + T Cells in Patients With Atherosclerotic Abdominal Aortic Aneurysm

Background—Cell-mediated immunity is considered to contribute to the pathogenesis of abdominal aortic aneurysms (AAA). In particular, infiltrating macrophages and CD8+ T lymphocytes participate in the destruction of the aortic wall extracellular matrix and smooth muscle cells. We surmise that these pathological events are controlled by circulating regulatory lymphocytes. Methods and Results—Circulating CD4+/CD31+ cells were reduced in AAA patients (n=80, 8.9±0.6%) as compared with controls (n=69, 13.7±0.8%; P<0.001) and inversely proportional to AAA size. Exclusion of the aneurysm by an endoprothesis did not affect CD31+ T cell values. Reduction of blood CD4+/CD31+ cells was not attributable to their enrichment in AAA tissue. In contrast, CD8+/CD31+ cells were slightly reduced in the blood while increased in the aneurysmal tissue (29.2±0.5 versus 20.2±4.7% in blood, n=6; P<0.05). Remarkably, high percentages of CD4+/CD31+ cells were able to regulate proliferation and cytokine production of CD8+ lymphocytes, as well as CD8+ cell-mediated cytotoxicity of aortic smooth muscle cells (P<0.01). Finally, CD4+/CD31+ cells reduced the production and activity of metalloproteinase-9 by lipopolysaccharide-stimulated macrophages. Conclusions—Circulating CD4+/CD31+ T cells regulate macrophage and CD8+ T cell activation and effector function in the arterial wall. Their reduction might promote the development of AAA.

Radial nerve compression by a large cephalic vein aneurysm: case report

A 43-year-old man had weakness of the extensor muscles in the right forearm and could not extend the right wrist. The apparent disorder was caused by radial nerve compression by a large aneurysm in the cephalic vein in the antecubital fossa. Surgical resection of the aneurysm resolved the symptoms. This exceedingly rare complication of venous aneurysm is discussed. Venous aneurysm should be included in the differential diagnosis of a subcutaneous mass, and diagnosis is best made with Duplex ultrasound scanning. Surgical excision is the appropriate treatment.

Management of pseudoaneurysm of the ascending aorta performed under circulatory arrest by port-access

Pseudoaneurysms of the ascending aorta following previous thoracic surgery pose a difficult surgical management problem. In this report, we present a case of a patient with aortic insufficiency and a pseudoaneurysm of the ascending aorta at the site of a previous anastomosis. The particularity of this case is in the atypical use of Port-Access technology (Heartport, Redwood City, CA) to overcome surgical concerns [1].

Ambulatory blood pressure profile after carotid endarterectomy in patients with ischaemic arterial disease.

Objective To assess the circadian blood pressure profile observed 3 months after endarterectomy. Design Twenty-five patients undergoing unilateral or bilateral carotid endarterectomy were compared with a control population of 20 patients, matched for age, sex, weight and drug therapy. Casual mean blood pressure measured by mercury sphygmomanometry was similar in both groups. Results Non-invasive ambulatory blood pressure monitoring showed that, whereas mean arterial pressure was identical in both groups, the group undergoing surgery had a significant increase in pulse pressure and its variability over 24 h. Such abnormalities predominated during the nocturnal period, in which the reduction in systolic blood pressure was less pronounced in the operated group than in controls. For all parameters there was no significant difference between subjects with unilateral or bilateral endarterectomy. Conclusion This study provides evidence that patients with carotid endarterectomy were characterized in the long term by an increase in the pulsatile component of blood pressure and its variability, in association with a disturbance in the physiological circadian rhythm. Such findings were not identified using casual blood pressure measurements.

Multiparametric attenuation and backscatter images for characterization of carotid plaque.

The goal of this study was to develop methods for quantitative ultrasound imagery suitable for noninvasive assessment of carotid plaque composition prior to the selection of the technique for revascularization. Using two broadband transducers (5–12 MHz and 12–28 MHz), backscattered radio frequency signals were acquired from entire lengths of 15 carotid endarterectomy specimens. Spectral analysis methods with correction for system response and beam diffraction were applied to radio frequency signals from local volumes of plaque having a 2 mm slice thickness, 1 mm width and axial depth of 480 μm and 240 μm at 10 MHz and 20 MHz, respectively. From these spectra, local values of four ultrasound parameters (integrated backscatter, frequency dependence of backscatter, integrated attenuation and slope of attenuation) were estimated and used to construct quantitative images. To combine information from these different parameter images, a two-step approach was followed. First, in 59 independent quantitative images of highly stenotic plaque, the average parameter values in a central five-by-three pixel region were correlated with plaque composition as assessed by histology to investigate the relationship between parameter values, frequency bandwidth and plaque composition. Discriminant analysis of parameter values vs. plaque composition was made to find a set of predictive equations to classify sets of measurements. Correct classification was obtained for 100% of calcified, 75% of intraplaque hemorrhage and 71 % of lipidic plaques of the input data set. Second, each set of pixels from different parameter images was classified using the predictive equations, and a single, local tissue composition image was constructed. Examples of tissue composition images are presented in comparison with corresponding histologic sections. Both agreement and disagreement between image pairs are discussed.

Proximal Scallop in Thoracic Endovascular Aortic Aneurysm Repair to Overcome Neck Issues in the Arch.

OBJECTIVE To evaluate initial experience with a custom made proximal scalloped stent graft for thoracic endovascular aortic repair (TEVAR) of aortic aneurysms involving the arch. METHODS Between September 2012 and November 2014, patients presenting with a thoracic aortic aneurysm (TAA) with short or angulated neck were selected for treatment by custom made proximal scalloped Relay Plus stent grafts (ABS Bolton Medical, Barcelona, Spain). Prospectively acquired data relating to patient demographics, procedure details, clinical outcomes, and complications were analyzed retrospectively. RESULTS Ten selected patients (50% male, mean age 77 ± 8 years) were treated using a thoracic custom made Relay Plus stent graft, three of whom underwent additional cervical supra-aortic trunk revascularizations. TAA were fusiform in four cases, saccular in three, and three patients were treated for proximal type I endoleaks after previous standard TEVAR. The graft was landed in zone 2 in 3 cases, in zone 1 in 4 cases, and in zone 0 in 3 cases. The custom made scallop was designed to preserve flow in the left subclavian artery in three patients, in the left common carotid artery in four, and in the innominate artery in three. No proximal type I endoleak occurred and proximal sealing was achieved in all cases, with a technical success rate of 100%. All targeted vessels were patent. During a mean follow up of 12 ± 5 months, no conversion to open surgical repair and no aortic rupture occurred. One patient died post-operatively from myocardial infarction and one patient suffered a stroke with complete recovery. One patient had a distal type I endoleak on the 6 month CT scan and is scheduled for distal extension. No paraplegia, retrograde dissection and no other aortic related complications were recorded. CONCLUSIONS Proximal scalloped stent grafts appear to be an effective additional tool for TEVAR of TAA when dealing with short or angulated proximal necks.