Patrick Feugier

Genes of Cholesterol Metabolism in Human Atheroma: Overexpression of Perilipin and Genes Promoting Cholesterol Storage and Repression of ABCA1 Expression

Objective—Accumulation of cholesterol in foam cells of atheroma plaques depends on the balance between uptake and efflux of cholesterol. It may also depend on proteins surrounding lipid droplets, adipophilin, and perilipins. They favor triglyceride storage in adipocytes and could play a similar role for cholesterol in atheroma. Methods and Results—We measured in human atheroma and nearby macroscopically intact tissue (MIT) the expression of perilipin, adipophilin, and regulatory factors of cholesterol metabolism. We identified perilipin A in human arterial wall. Its expression was largely increased in atheroma compared with MIT, and perilipin was present in macrophages and vascular smooth muscle cells. Adipophilin, ACAT1, and CD36 were also overexpressed in atheroma. mRNA levels of low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and SREBP-2 were unchanged. With respect to efflux of cholesterol, the mRNA levels of NCEH and ABCA-1 were unchanged, whereas CLA-1 mRNA was slightly higher in atheroma. Importantly, immunoblotting of ABCA-1 showed a dramatic decrease of ABCA1 protein, the key molecule of cholesterol efflux, in atheroma compared with MIT. Conclusion—We show the presence and induction of perilipin in atheroma. This overexpression and the coordinated modifications of expression of key regulatory factors for cholesterol metabolism could favor cholesterol accumulation.

Effect of abdominal aortic grafts on aortic stiffness and central hemodynamics

Graft-prosthesis and stentgraft placements are effective modalities for treating abdominal aortic aneurysm, but related changes in arterial stiffness are not well established. The present study sought to assess aortic stiffness after aneurism repair by measuring pulse wave velocity (PWV). The graft-related variation of carotid–femoral PWV was compared with that of carotid–radial PWV, the latter being unaffected by vascular treatment. The secondary objective was to evaluate potential differences between graft-prosthesis and stentgraft in terms of aortic stiffness and augmentation index, a composite indicator integrating wave reflexion. Fifty patients were included (39 had a graft-prosthesis and 11 had a stentgraft). In the whole group and after a median postoperative follow-up of 47 days, carotid–femoral PWV increased by +1.0 m/s [−12.3, +10.3], while carotid–radial PWV slightly decreased by −0.3 m/s [−4.4; +3.5] (P = 0.001). The effect of the type of prosthesis on the PWV was not significant. Nevertheless, the augmentation index increased after stentgraft implantation (+4% [−10; +17]) and decreased after graft-prosthesis placement (−8.5% [−47; +17]) (P < 0.01). This difference was not explained by a heart rate or a treatment effect and was likely attributable to the prosthesis per se. This study demonstrates the impact of aortic grafts on aortic stiffness. Besides, it suggests that stentgraft increases reflected waves more than graft-prostheses. These changes of vascular properties may influence the outcomes after surgery.

Early and Late Results of Contemporary Management of 37 Secondary Aortoenteric Fistulae

PURPOSE Evaluate the results of the two modalities used for the treatment of Secondary Aorto-Enteric Fistula (SAEF): In situ Reconstruction (ISR) and Extra-Anatomic Reconstruction (EAR). The primary endpoints of this study were early standard 30-day mortality and reinfection (RI). Secondary endpoints were perioperative morbidity, late mortality, primary graft patency, and major amputation rates. MATERIAL & METHOD Diagnosis of SAEF was based on clinical examination and the results of pre-operative duplex or CT scans. Surgical management was performed according to local protocols at the participating institutions: - Elective surgery: ISR or staged EAR. - Emergency surgery: aortic clamping followed by ISR or EAR. - Selected high-risk patients: endovascular repair. Statistical analyses were performed using the actuarial method. Univariate analysis was used for analysis of categorical variables, and multivariate analysis was performed with a Cox proportional hazard regression. RESULTS A total of 37 patients were included in this retrospective multicentre study. Mean follow-up was 41 months. The majority of the patients (20, 54%) presented acutely. EAR was performed in 9 patients (24%), ISR in 25 (68%), and 3 patients underwent endovascular repair. Bacteriological cultures were negative in 3 patients (9%). The most frequent organisms identified were Candida species and Escherichia coli. The 30-day mortality was 43% (16 patients). Patient age (>75 years) was the sole predictive factor associated with operative mortality (p = 0.02); pre-operative shock was not statistically significant (p = 0.08). There were 2 graft thromboses and 1 femoral amputation. Primary graft patency was respectively 89% at 1 year and 86% at 5 years; limb salvage rates were 100% at 1 and 5 years and 86% at 6 years, with no difference between ISR and EAR. RI occurred after 9.3 ± 13 months in 8 of 17 surviving patients and was fatal in all cases. For all surviving patients, the RI rate at 1 and 2 years was 24% and 41% respectively. There was no significant difference in the rate of RI after ISR or EAR. CONCLUSION EAR does not appear to be superior to ISR. The risk of RI increased with the length of follow-up, irrespective of the treatment modality. Life-long surveillance is mandatory. Our results with endovascular sealing of SAEF should be considered a bridge to open repair.

Editor's Choice – Hybrid Treatment of Thoracic, Thoracoabdominal, and Abdominal Aortic Aneurysms: A Multicenter Retrospective Study

OBJECTIVES The aim of this study was to assess the results of hybrid techniques for the treatment of thoracic, thoracoabdominal, and abdominal aortic aneurysms based on multicenter results and the various series regarding hybrid procedures reported in the literature. METHODS The results of 76 hybrid procedures performed in 19 French university hospital centers between November 2001 and October 2011 were collected. There were 50 men and 26 women, mean age 68.2 (35-86) years. All patients were considered at high risk (ASA≥3) for conventional surgery. Aneurysms involved the thoracic, abdominal, and thoracoabdominal aorta in five, 14, and 57 cases respectively. There were 11 emergent repairs. The revascularization of four visceral arteries was performed in 38 cases. Between one and three visceral arteries were revascularized in the other cases. Visceral artery debranching and stent graft deployment were performed in a one-stage procedure in 53 cases and in a two-stage procedure in 23 cases. RESULTS There were 26 (34.2%) postoperative deaths. Nine of the survivors developed paraplegia, of which one resolved completely. Bowel ischemia occurred in 13 cases (17.1%), and one patient was treated by a superior mesenteric artery bypass. Four patients required long-term hemodialysis. Postoperative computed tomography scan showed a type II endoleak in two patients. CONCLUSIONS Morbidity and mortality in this study were greater than previously reported. Candidates for hybrid aortic repair should be carefully selected.

Cathepsin G is associated with atheroma formation in human carotid artery.

Objective To elucidate the organization of the tissue angiotensin system, we investigated the expression and cellular localization of angiotensin system components and cathepsins D and G, potentially involved in intraparietal angiotensin II formation and atheroma. Methods Total RNA was extracted from atheroma plaque, fatty streaks and macroscopically intact tissue obtained during carotid endarterectomy in 21 hypertensive patients. mRNA levels were compared between these tissues using a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In situ hybridization and immunohistochemistry were used to define the cellular localization of the transcripts and their respective proteins. Results Apart from renin and angiotensin type 2 (AT2) receptors, which were never detected, the studied mRNAs could be measured in all patients. Angiotensin-converting enzyme (ACE) mRNA was increased five-fold in atheroma, and angiotensin type 1 receptor (AT1) mRNA decreased 2.5-fold in atheroma and 1.4-fold in fatty streaks compared to intact tissue. A two-fold increase in cathepsin G mRNA was observed in atheroma plaque. In atheroma and intact tissue, significant positive correlations were found between cathepsin G and angiotensinogen, AT1 receptor and ACE mRNAs. Angiotensinogen and cathepsin mRNAs and proteins were detected in both arterial layers. AT1 immunoreactivity was mainly associated with α-actin-positive cells. Conclusion All components required for angiotensin II formation are expressed locally in the arterial wall, where, in the absence of renin, cathepsin G could be a major angiotensin-generating enzyme. Overexpression of ACE and cathepsin G may lead to angiotensin II overproduction and contribute, with decreased number of differentiated smooth muscle cells, to the lower amount of AT1 receptor in atheroma.

Increased Insulin-Stimulated Expression of Arterial Angiotensinogen and Angiotensin Type 1 Receptor in Patients With Type 2 Diabetes Mellitus and Atheroma

Objective—Because inhibition of the renin–angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients. Methods and Results—mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2- to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5- and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1–2 was 4-fold higher in MIT from T2D than from CTR patients. Conclusions—The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1–2 pathway by insulin.

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.

Medical treatment of prosthetic vascular graft infections: Review of the literature and proposals of a Working Group

More than 400000 vascular grafts are inserted annually in the USA. Graft insertion is complicated by infection in 0.5-4% of cases. Vascular graft infections (VGIs) are becoming one of the most frequent prosthesis-related infections and are associated with considerable mortality, ranging from 10 to 25% within 30 days following the diagnosis. Treatment of VGI is based on urgent surgical removal of the infected graft followed by prolonged antibiotherapy. Data regarding the best antibiotherapy to use are lacking since no well designed trial to study antimicrobial treatment of VGI exists. Moreover, since VGIs demonstrate very specific pathophysiology, guidelines on other material-related infections or infective endocarditis treatment cannot be entirely applied to VGI. A French multidisciplinary group gathering infectious diseases specialists, anaesthesiologists, intensivists, microbiologists, radiologists and vascular surgeons was created to review the literature dealing with VGI and to make some proposals regarding empirical and documented antibiotic therapy for these infections. This article reveals these proposals.

Angioplasty of the Common Femoral Artery and Its Bifurcation

BACKGROUND To evaluate the efficacy of percutaneous transluminal angioplasty (PTA) of atherosclerotic lesions of the common femoral artery (CFA) and its bifurcation. METHODS From 2009 to 2013, 53 patients (43 men, average age, 68 years) were included in a single-center, nonrandomized, prospective study. Indication was disabling intermittent claudication (n = 36) or chronic critical limb ischemia (n = 17). Thirty-four procedures (64%) were isolated CFA PTA, whereas 7 of 53 (13%) involved inflow (including 4 iliac occlusions) and 12 of 53 (23%) involved outflow vessels. Primary stenting was performed in 50 cases (95%). CFA occlusions were recanalized in 4 of 53. Lesions involved the bifurcation in 22 cases (40%). Follow-up consisted of clinical examination and duplex scanning with ankle-brachial index measurement at 1, 6, and 12 months. A biplane X-ray was performed at 1 year. The primary end point was the absence of binary restenosis (>50% reobstruction of the CFA). Secondary end points were freedom from target lesion revascularization (TLR) and stent fracture rate. RESULTS Procedural success was achieved in 96% of cases. At a mean follow-up of 24 months (with 1 patient lost of follow-up), the absence of binary restenosis was 92.5%. At the end of follow-up, 82% of patients continued to show clinical improvement. Freedom from TLR was 97%. Stent fracture rate at 1 year was 9%. CONCLUSIONS PTA of the CFA and its bifurcation is a reliable technique with good midterm functional results. These results justify performing a randomized study comparing surgery and endovascular treatment.