[THROMBOANGIITIS OBLITERANS (BUERGER'S DISEASE)]. / Maladie de Buerger.

To day there appears to be a consensus to recognize thromboangiftis obliterans (Buerger's disease) as a distinct clinical and pathological entity, characterized by an inflammatory occlusive vasculitis of the small and medium-sized arteries and veins that affects young adult smokers. The strong link with smoking is one of the unique features of thromboangiitis obliterans. Once the disease has became established stepping smoking is the only effective way to prevent evolution of the disease and to reduce the risk of major amputations. Ischaemia of the lower and upper limbs and superficial thrombophlabitis are the essential features of the clinical presentation. However the diagnosis of thromboangiitis is rendered difficult by the lack of specific clinical, radiological, biological and histapathological features. Thus the diagnosis is funded on a probabilistic approach. Discontinuation of tobacco use and to day cannabis are the cornerstone of therapeutic management of patients with thromboangiitis. In patients with ischaemic lesions local care is the other main component of therapeutic management, infusion of iloprost had demonstrated some efficacy.

Efficacy and tolerance of infliximab in refractory Takayasu arteritis: French multicentre study.

OBJECTIVE: To analyse the efficacy and tolerance of infliximab in refractory Takayasu arteritis (TA). METHODS: French multicentre retrospective study that included patients with TA. Clinical disease activity was defined as new vascular and/or constitutional signs. RESULTS: Fifteen patients with TA [median age 41 (range 17-61) years; 13 women] were included. At initiation of infliximab therapy, 14 patients were treated with CSs [prednisone; median dose 20 (range 5-35) mg/day], MTX (n = 7) or AZA (n = 4). Infliximab was used at median 5 (range 3-5) mg/kg at a median of every 6 (range 4-8) weeks. A partial or good overall response was noted in 13 (87%) of the 15 cases, 10 (77%) of the 13 cases and 8 (73%) of the 11 cases at 3, 6 and 12 months, respectively. Clinical and biological activities significantly decreased within 3 months (from 11 at baseline to 4 patients at 12 months; P < 0.05), and similarly for CS dose [from median 20 (range 5-35) mg/day at baseline to median 6 (range 2.5-30) mg/day at 12 months; P < 0.05]. Only one patient was still steroid-dependent at 12 months (vs 8 cases before infliximab). CRP regressed from a median 30 (range 4-70) mg/l to 5 (range 0-57) mg/l and 6 (0-50) mg/l at 3 and 6 months, respectively (P < 0.05). Side effects were two infusion-related reactions, one pulmonary tuberculosis, one severe bacterial infection and EBV reactivation. CONCLUSION: This study confirms the interest of infliximab in terms of clinical and biological response, as well as the steroid-sparing effect in TA.

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.

BACKGROUND: Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a ß(1)-adrenoceptor antagonist with a ß(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. METHODS: Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptritrated by 100 mg steps every 6 months to a maximum of 400 mg per day. [DOSAGE ERROR CORRECTED]. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. FINDINGS: 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15-0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. INTERPRETATION: We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. FUNDING: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

[Raynaud's phenomenon, disease or syndrome?]. / Phénomène de Raynaud, maladie ou syndrome?

Raynaud's phenomenon is a common symptom. More often it is usually an idiopathic and benign condition. But it can be an early manifestation of a connective tissue disease especially scleroderma and primary Sjogren's syndrom. Thus it is necessary to develop reasonable screening model. If the vasomotor symptoms are localized, a diagnosis of secondary Raynaud's phenomenon is highly probable and the main etiology is an arterial disease. Occupational arterial lesions are a particularly aspect of secondary Raynaud's phenomenon. Calcium channel blockers are the reference for the symptomatic treatment of Raynaud's phenomenon. In severe secondary forms, intravenous iloprost infusion is effective. New drugs as endothelin antagonist and phospodiesterase type 5 inhibitors are still to be evaluated.

Thromboangiitis obliterans and endothelial function.

BACKGROUND: Endothelial dysfunction may be involved in the pathophysiology of thromboangiitis obliterans (TAO). This study compares endothelial function and large artery stiffness between 10 TAO patients assessed during an exacerbation phase and 10 age- and sex-matched control subjects. MATERIAL AND METHODS: Flow-mediated vasodilation after gradual hand skin heating (from 28 degrees C to 44 degrees C) and endothelium-independent vasodilation after sublingual administration of 150 microg glyceryl trinitrate (GTN) were studied using a high-resolution echotracking system to simultaneously measure the brachial artery (BA) diameter and changes in wall shear stress. Aortic stiffness was assessed by carotid-to-femoral pulse wave velocity. RESULTS: The baseline BA diameter was significantly smaller in TAO patients (3599 +/- 668 microm) than in control subjects (4114 +/- 671, P = 0.04). Hand warming caused a linear increase in shear stress accompanied by a linear increase in BA diameter as a function of increasing temperature for TAO patients and control subjects. There was no significant difference between the two groups [relative increase in BA diameter: + 9.3% (-0.1 to 11.5) vs. + 4.8% (3.0 to 8.1), respectively; P = 0.63]. The slope of the BA diameter vs. shear stress relationship did not significantly differ between the two groups. The relative increase in the BA diameter after GTN was significantly greater in TAO patients than in controls [+ 30.8% (28.6 to 33.6) vs. + 16.2% (12.6 to 21.9) respectively; P = 0.02]. Finally, TAO patients had greater aortic stiffness than control subjects (9.81 +/- 1.72 m s(-1) vs. 7.82 +/- 0.84 m s(-1) respectively; P = 0.0052). CONCLUSIONS: Acute TAO is characterised by vasoconstriction and increased aortic stiffness in the absence of changes in flow-mediated dilation.

[New oral anticoagulants: prospects]. / Nouveaux antithrombotiques: perspectives.

Two new oral anticoagulants are licensed in France for prevention for venous thromboembolism in patients undergoing hip or knee arthroplasty. Dabigatran (Pradaxa) inhibits the active site of thrombin. The 220-mg dose is recommended for the majority of patients whereas the 150-mg dose is reserved for patients also taking amiodarone and for those at higher risk for bleeding (patients with moderate renal insufficiency). Rivaroxan (Xarelto) inhibits reversibly the active site of fXa, the 10 mg-dose once daily is recommended started 6 to 12 hours after wound closure. The two drugs are given once daily in fixed doses without coagulation monitoring. However the aim of the new anticoagulants is to replaced VKAs particularly for prevention of stroke in patients with auricular fibrillation and for the treatment of venous thrombo-embolism. Recently published results in these two indications with dabigatran are very promising.

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.

[Vascular Ehlers-Danlos syndrome]. / Syndrome d'Ehlers-Danlos vasculaire.

The vascular type of Ehlers-Danlos syndrome (EDS) is a rare genetic disease transmitted as an autosomal dominant trait. It is distinguished from other forms of EDS by its unstable acrogeric morphotype and by vascular, gastrointestinal, and obstetrical complications. Diagnosis is based on various clinical signs, noninvasive imaging, and on the identification of a mutation of the COL3A1 gene, which provides diagnostic certainty but has a sensitivity of only 61%. When two major diagnostic criteria are present, a genetic test should be proposed, performed and its result presented in a multidisciplinary group. The precautionary principle requires that preventive measures be implemented when the diagnosis is suspected. All artery puncture, surgery, and gastrointestinal and uterine endoscopy are contraindicated, permissible only in life-threatening emergencies. Straining against a closed glottis and all other situations or drugs likely to raise blood pressure must be avoided. Contraception must be discussed to avoid pregnancy during the diagnostic period. Arterial lesions suggestive of the disease include dissecting aneurysms of the internal carotid and iliac arteries and of the anterior visceral branches of the abdominal aorta, fusiform aneurysms of the splenic artery, and early onset nontraumatic direct carotid-cavernous fistulae. Early-onset varicose veins, spontaneous peritonitis or unusually important perineal lesions after giving birth should also attract the physician's attention. Psychological treatment and support of patients and their families is essential, to help them both to live with their disease and to deal with the information and screening issues. The prognosis of Ehlers-Danlos syndrome, vascular type, is grim but there is wide interindividual variability and life expectancy is best among patients receiving regular follow-up. Management by an experienced multidisciplinary team, implementation of drastic prevention measures and, depending on the results of the BBEST study, the possible prescription of beta-blockers should help to reduce the risk of complications and justify hope for a real improvement in prognosis in the near future.

[Medical treatment of critical leg ischemia: current status and future perspectives of gene and cell therapy]. / Ischémie critique des membres inférieurs: traitement médical actuel et perspectives de la thérapie génique et cellulaire.

Critical limb ischemia (CLI) is associated with a high risk of amputation and death. For patients who cannot be surgically revascularized, medical options include prostanoids, spinal cord stimulation and lumbar sympathectomy, but none of these treatments has a demonstrated impact on the amputation rate at six months. Gene and cell therapy, aimed at stimulating angiogenesis, have mainly been tested in phase I and II clinical trials. These approaches appear to be feasible and safe in the short-term, but large randomized studies are necessary to demonstrate their clinical benefits and long-term safety.

P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study.

BACKGROUND: We recently described a gain-of-function haplotype, called H2, of the adenosine diphosphate (ADP) receptor P2Y12 gene associated with increased ADP-induced platelet aggregation ex vivo in healthy volunteers. Because platelets play a key role in atherosclerosis and arterial thrombosis, we tested the possible link between the H2 haplotype and the risk of peripheral arterial disease (PAD) in a case-control study. METHODS AND RESULTS: We studied 184 consecutive male patients under 70 years of age with PAD and 330 age-matched control subjects free of symptomatic PAD and with no cardiovascular history. Mean age was 57.1+/-7.2 years (cases) and 56.7+/-7.6 years (control subjects). The H2 haplotype was more frequent in patients with PAD than in control subjects (30% and 21%, respectively; OR, 1.6; CI, 1.1 to 2.5; P=0.02 in univariate analysis). This association with PAD remained significant in multivariate regression analysis (OR, 2.3; CI, 1.4 to 3.9; P=0.002) after adjustment for diabetes, smoking, hypertension, hypercholesterolemia, and other selected platelet receptor gene polymorphisms. CONCLUSIONS: These data point to a role of the H2 haplotype in atherosclerosis and raise the possibility of relative thienopyridine resistance in carriers of the P2Y12 H2 haplotype.

Increased carotid wall stress in vascular Ehlers-Danlos syndrome.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS), also known as EDS type IV, an inherited disorder of connective tissue, results from mutations in the gene encoding type III procollagen (COL3A1). Affected patients are at risk for arterial dissection or rupture, the main cause of death. To understand the pathogenesis of the vascular lesions, we used a biomechanical approach and determined steady and pulsatile wall stress. METHODS AND RESULTS: Sixteen patients with vEDS and 16 age-, gender-, and blood pressure-matched control subjects were included in this cross-sectional noninvasive study. Circumferential wall stress was determined under steady and pulsatile conditions at the site of an elastic (common carotid) and a muscular (radial) artery from the measurements of intima-media thickness and internal diameter with high-resolution echo-tracking systems and either mean blood pressure or pulse pressure, respectively. At the site of the carotid artery, steady circumferential wall stress was 43% higher in vEDS patients than in control subjects (68.9+/-14.3 versus 48.2+/-12.1 kPa, P<0.001), and pulsatile circumferential wall stress was 22% higher (28.2+/-7.7 versus 23.1+/-5.7 kPa, P<0.001). Carotid intima-media thickness was 32% lower (408+/-56 versus 598+/-171 microm, P<0.001) in vEDS patients, and internal diameter was not different between groups. Radial artery parameters were not significantly different between groups. CONCLUSIONS: In vEDS patients, an abnormally low intima-media thickness generates a higher wall stress than in control subjects at the site of an elastic artery, which may increase the risk of arterial dissection and rupture.

Extended venous thromboembolism prophylaxis after total hip replacement: a comparison of low-molecular-weight heparin with oral anticoagulant.

BACKGROUND: Oral anticoagulants and low-molecular-weight heparin are both recommended for venous thromboembolism prophylaxis after total hip replacement. To date, these regimens have not been compared by means of clinical end points in the extended prophylaxis setting. METHODS: We randomly assigned 1279 patients 3 days after total hip replacement surgery to fixed-dose subcutaneous low-molecular-weight heparin (reviparin sodium, 4200 anti-Xa IU) or adjusted-dose oral anticoagulant (international normalized ratio, 2-3; acenocoumarol) for a 6-week period. The primary end point was the failure rate, defined as the combined clinical events of a confirmed symptomatic thromboembolic event, a major hemorrhage, or death. All patients were followed up throughout the study interval. The primary objective was to compare the observed cumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group. RESULTS: In the intent-to-treat population, objectively documented symptomatic thromboembolic events occurred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.30; 95% confidence interval for the difference, -0.8% to 2.8%). Major bleeding occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of 636 patients receiving low-molecular-weight heparin or oral anticoagulants, respectively (P =.001). The failure rate was 24 (3.7%) of 643 patients compared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants (P =.001). CONCLUSIONS: A significantly higher benefit-risk ratio was observed for patients undergoing elective hip replacement who received extended out-of-hospital prophylaxis with low-molecular-weight heparin vs acenocoumarol. Low-molecular-weight heparin prophylaxis was at least as effective as oral anticoagulants, but with a marked improvement in safety.