Adenosine Receptors Profile in Fibromuscular Dysplasia.

Fibromuscular dysplasia (FMD) is a non-inflammatory vascular disease that is characterized by unexplained systemic hypertension occurring in young people, associated with arterial stenosis, aneurysm rupture, intracranial/renal infarction, and stroke. Although the gold standard for the diagnosis remains catheter-angiography, biological markers would be helpful due to the delay from first symptom to diagnosis. Adenosine is an ATP derivative, that may be implicated in FMD pathophysiology. We hypothesized that changes in adenosine blood level (ABL) and production of adenosine receptors may be associated with FMD. Using peripheral blood mononuclear cells, we evaluated A1, A2A, and A2B receptor production by Western blot, in 67 patients (17 men and 50 women, mean (range) age 55 (29−77) years and 40 controls, 10 men and 30 women, mean (range) age 56 (37−70)). ABL was evaluated by liquid chromatography, mass spectrometry. ABL was significantly higher in patients vs. controls, mean (range): 1.7 (0.7−3) µmol/L vs. controls 0.6 (0.4−0.8) µmol/L (+180%) p < 0.001. While A1R and A2AR production did not differ in patients and controls, we found an over-production of A2BR in patients: 1.70 (0.90−2.40; arbitrary units) vs. controls = 1.03 (0.70−1.40), mean + 65% (p < 0.001). A2BR production with a cut off of 1.3 arbitrary units, gives a good sensitivity and specificity for the diagnosis. Production measurement of A2BR on monocytes and ABL could help in the diagnosis, especially in atypical or with poor symptoms.

Controversies about the systematic preoperative pharmacological treatment before pheochromocytoma or paraganglioma surgery.

The question of systematic use of a pharmacological treatment before surgery in patients diagnosed with pheochromocytoma and paraganglioma (PPGL) remains highly controversial. While recent guidelines suggest that this should be used in all patients, some experienced teams consider it unnecessary in some cases, provided the surgery is performed in a dedicated center that has expert endocrinologists, cardiologists, surgeons, and anesthetists. This controversy is aimed at shedding light on the potential benefits and risks of such a treatment, focusing specifically on alpha blockers which are considered as the first-line medical treatments in patients with PPGL. After discussing the rationale for alpha blockers, hemodynamic instability, tolerance, and acute cardiac complications will then be discussed in the first part of the manuscript, defending a systematic use. The second section will focus on blood pressure control, tolerance of alpha blockers, and also the management of normotensive PPGL, examining the daily risks of PPGL and arguing against the systematic use of a preoperative pharmacological treatment before surgery. Finally, we will discuss the concept of expert centers and define the patients in whom the risk/benefit profile would favor the use of this preoperative treatment.

Insights from intravascular pressure measurement of renal artery revascularization in patients with fibromuscular dysplasia: The DYSART study.

OBJECTIVE: The indication of percutaneous renal transluminal angioplasty (PTRA) in fibromuscular dysplasia (FMD) is mainly based on renal artery stenosis (RAS) due to atherosclerosis criteria, which are not specific to FMD. Consequently, the selection of patients who could benefit from this treatment and its effectiveness remain uncertain. The aims of this study were to: (1) report the effects of PTRA guided by trans-stenotic pressure measurements on hypertension 7 months after treatment; (2) assess the impact of pressure measurement to guide treatment efficacy in comparison to visual angiographic parameters; and (3) evaluate the reproducibility and accuracy of the stenosis measurement using a 4F catheter in comparison to a pressure guidewire. METHODS: This prospective multi-centric study analyzed 24 patients with hypertension with RAS due to FMD that required PTRA. Clinical, duplex ultrasound, and angiographic indices were collected, and patients were followed up for 7 months (±1 month). Angiographic indices were measured twice both by a pressure guidewire and a 4F catheter. Assessment of procedural and clinical success of angioplasty was performed for all patients. RESULTS: Twenty-three patients (96%) had procedural success (considered as a post-PTRA translesional systolic gradient ≤10 mmHg or reduced by at least 80%) with a significant decrease in the systolic gradient after angioplasty (26.50 mmHg; [interquartile range, 16.75-38.75] vs 0.00 [interquartile range, 0.00-2.00]; P < .01). Three patients (12%) had complications, including two renal artery dissections and one partial renal infarction. Twenty-one patients (88%) were clinical responders to angioplasty at follow-up. Visual stenosis assessment showed a poor correlation with systolic gradient measurement before and after PTRA (R from -0.05 to 0.41; P = 0.06-0.82). High correlations were found between pressure measurements made by a 4F catheter and guidewire (R from 0.64 to 0.89; P ≤ .003). CONCLUSIONS: In patients selected by clinical indicators and duplex ultrasound, reaching a translesional systolic gradient ≤10 mmHg or reduced by at least 80% after angioplasty, promotes a high success rate for PTRA in hypertension due to FMD RAS.

Use of Direct Oral Anticoagulants in Patients with Sickle Cell Disease and Venous Thromboembolism: A Prospective Cohort Study of 12 Patients.

Patients with sickle cell disease have an increased risk of venous thromboembolism (VTE) and with a mortality 2-fold higher. The anticoagulation of VTE in a young population is an important question. Indeed, hemorrhagic complications of anticoagulation may occur more frequently than in the general population. The use of a direct oral anticoagulant (DOAC) is not recommended for VTE in patients with sickle cell disease because those patients were not included in the clinical studies. We aimed to study the safety of using DOACs in a prospective cohort of patients with sickle cell disease and VTE. We prospectively followed the cohort of all sickle cell disease patients undergoing recent DOAC treatment for VTE at a sickle cell disease reference center. Twelve patients received rivaroxaban for VTE (eight women and four men). The median age was 27 years (20-45). The sickle cell disease variants included homozygous Hb SS (HBB: c.20A>T) in eight patients, Hb S-ß+-thalassemia (Hb S-ß+-thal) in two, Hb S-ß0-thal in one and Hb S-Hb C (HBB: c.19G>A) in one. The cumulative duration of follow-up was 3134 days under rivaroxaban treatment. There were two thrombotic events, including a patient with a double positivity of antiphospholipid antibodies. No major bleeding was observed, and 6/12 patients presented minor bleeding (epistaxis: n = 4; anal fissure bleeding: n = 1; menorrhagia n = 4). Of these, 3/6 required their treatment to be switched to apixaban, which stopped the bleeding. Direct oral anticoagulants may be an alternative treatment for VTE in patients with sickle cell disease, except for an associated antiphospholipid syndrome.

Stem cell properties of peripheral blood endothelial progenitors are stimulated by soluble CD146 via miR-21: potential use in autologous cell therapy.

Cell-based therapies constitute a real hope for the treatment of ischaemic diseases. One of the sources of endothelial progenitors for autologous cell therapy is Endothelial Colony Forming Cells (ECFC) that can be isolated from peripheral blood. However, their use is limited by their low number in the bloodstream and the loss of their stem cell phenotype associated with the acquisition of a senescent phenotype in culture. We hypothesized that adding soluble CD146, a novel endothelial growth factor with angiogenic properties, during the isolation and growth procedures could improve their number and therapeutic potential. Soluble CD146 increased the number of isolated peripheral blood ECFC colonies and lowered their onset time. It prevented cellular senescence, induced a partial mesenchymal phenotype and maintained a stem cell phenotype by stimulating the expression of embryonic transcription factors. These different effects were mediated through the induction of mature miR-21. When injected in an animal model of hindlimb ischaemia, sCD146-primed ECFC isolated from 40 ml of blood from patients with peripheral arterial disease were able to generate new blood vessels and restore blood flow. Treatment with sCD146 could thus constitute a promising strategy to improve the use of autologous cells for the treatment of ischaemic diseases.

Exercise transcutaneous oximetry significantly modifies the diagnostic hypotheses and impacts scheduled investigations or treatments of patients with exertional limb pain.

INTRODUCTION: In lower extremity peripheral artery disease (PAD), transcutaneous oximetry at exercise (Ex-TcpO2) has been largely validated in research practice, but evidence of routine practice in various vascular laboratories is missing. We hypothesized that Ex-TcPO2 would change the diagnosis hypotheses, investigations and treatments for patients referred for exertional limb pain. MATERIAL & METHODS: A multicenter prospective trial was conducted in nine different referral centers. Investigators performed Ex-TcpO2 and recorded investigations and treatments already scheduled for the patient. We encoded referral physician's diagnostic hypothesis. Before Ex-TcpO2, vascular physicians were asked to give their diagnosis hypotheses. A minimal decrease from rest of oxygen pressure (DROP)

Autologous Bone Marrow Mononuclear Cell Implantation and Its Impact on the Outcome of Patients With Critical Limb Ischemia　- Results of a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Cell therapy is a therapeutic option for patients presenting with nonrevascularizable critical limb ischemia (CLI). However there is a lack of firm evidence on its efficacy because of the paucity of randomized controlled trials.Methods and Results:The BALI trial was a multicenter, randomized, controlled, double-blind clinical trial that included 38 patients. For all of them, 500 mL of bone marrow were collected for preparation of a BM-MNC product that was implanted in patients assigned to active treatment. For the placebo group, a placebo cell-free product was implanted. Within 6 months after inclusion, major amputations had to be performed in 5 of the 19 placebo-treated patients and in 3 of the 17 BM-MNC-treated patients. According to a classical logistic regression analysis there was no significant difference. However, when using the jackknife analysis, 6 months after inclusion BM-MNC implantation was associated with a lower risk of major amputation (odds ratio (OR): 0.55; 95% confidence interval (CI): 0.52-0.58; P<0.0001) and of occurrence of any event (major or minor amputation, or revascularization) (OR: 0.30; 95% CI: 0.29-0.31; P<0.0001). The secondary endpoints (i.e., pain, ulcers, TcPO2, and ankle-brachial index value) were not statistically different between groups. CONCLUSIONS: Our results suggested that cell therapy reduced the risk of major amputation in patients presenting with nonrevascularizable CLI.

Mortality associated with systemic lupus erythematosus in France assessed by multiple-cause-of-death analysis.

OBJECTIVE: To assess the mortality profile of systemic lupus erythematosus (SLE) patients in France using multiple-cause-of-death analysis. METHODS: Data were collected between 2000 and 2009 in the French Epidemiological Center for the Medical Causes of Death database, and death certificates issued upon the death of an adult for whom SLE was an underlying cause of death (UCD) or a non-underlying cause of death (NUCD) were evaluated using multiple-cause-of-death analysis. Sex, age, sex ratio, standardized mortality rates, as well as frequency of the various causes of death were assessed, at both a national and a regional level. For the main causes of death, the observed number of deaths in relation to the expected number of deaths (O:E ratio) (standardized for age and sex) was calculated. RESULTS: During the study period, 1,593 deaths related to SLE were identified. The mean ± SD age at death was 63.5 ± 18.4 years and the sex ratio (female:male) was 3.5. The mean standardized mortality rate was 3.2 per 1 million people (range 2.7-4.1). When SLE was the UCD (n = 637), the main NUCDs were cardiovascular diseases (49.5%), infectious diseases (24.5%), and renal failure (23.2%). When SLE was an NUCD (n = 956), the most common UCDs were cardiovascular diseases (35.7%), neoplasms (13.9%), and infectious diseases (10.3%). The overall O:E ratio was >1 for infectious and cardiovascular diseases and renal failure (especially among people <40 years of age for the latter 2 causes), but was <1 for neoplasms. CONCLUSION: Cardiovascular disease is the leading cause of death associated with SLE in France.

Secondary procedures after infrarenal abdominal aortic aneurysms endovascular repair with second-generation endografts.

BACKGROUND: To study the incidence, the types, and the results of secondary procedures performed after endovascular treatment of infrarenal abdominal aortic aneurysm (AAA). To compare the population of patients who underwent secondary procedure (P2) with the population of those who did not require it. MATERIAL AND METHODS: Between 1998 and 2008, this study included all the patients electively treated for AAA with stentgrafts that were still available on the market on January 1, 2009. Data were prospectively collected and retrospectively analyzed. The postoperative follow-up included at least a systematic computed tomography scan at 6, 12, 18, and 24 months and then every year. P2 were defined as any additionnal procedures performed to treat aneurysm related complications after initial stentgraft implantation. RESULTS: We studied 162 patients with a mean 40 ± 31 months' follow-up. In 32 patients (19.7%), there were 46 P2, 3 of them were surgical conversion and 1 with endovascular conversion. Thirty-nine P2 were scheduled, and seven were performed in emergency. Nine patients underwent more than one P2. P2 was indicated for type II endoleak in 17 cases, 13 of them with a diameter increase; for type I endoleak in 10 cases; for AAA rupture in 3 cases; for occlusion or stentgraft stenosis in 13 cases; and for 1 type III endoleak, 1 endotension, and 1 femoro-femoral crossover bypass infection. Two ruptures occurred in patients who had undergone P2. The immediate technical success was 89.1%. At 30 days, morbidity was 10.9%, and there was no mortality. Survival rates at 3 and 5 years were respectively 85.2% and 71.9% in patients with secondary procedure and 70.6% and 47.5% in the others (p = 0.046). CONCLUSIONS: In patients treated for AAA with second generation stentgrafts, in the long term, secondary procedure rate was 19.7%. Survival rate for patients who underwent a secondary procedure was better, which was probably related to the fact that they were younger at the time of stentgraft implantation. Large AAA diameter was a secondary-procedure risk factor.

A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants.

Low birth weight (LBW) is associated with increased risk of cardiovascular diseases at adulthood. Nevertheless, the impact of LBW on the endothelium is not clearly established. We investigate whether LBW alters the angiogenic properties of cord blood endothelial colony forming cells (LBW-ECFCs) in 25 preterm neonates compared with 25 term neonates (CT-ECFCs). We observed that LBW decreased the number of colonies formed by ECFCs and delayed the time of appearance of their clonal progeny. LBW dramatically reduced LBW-ECFC capacity to form sprouts and tubes, to migrate and to proliferate in vitro. The angiogenic defect of LBW-ECFCs was confirmed in vivo by their inability to form robust capillary networks in Matrigel plugs injected in nu/nu mice. Gene profile analysis of LBW-ECFCs demonstrated an increased expression of antiangiogenic genes. Among them, thrombospondin 1 (THBS1) was highly expressed at RNA and protein levels in LBW-ECFCs. Silencing THBS1 restored the angiogenic properties of LBW-ECFCs by increasing AKT phosphorylation. The imbalance toward an angiostatic state provide a mechanistic link between LBW and the impaired angiogenic properties of ECFCs and allows the identification of THBS1 as a novel player in LBW-ECFC defect, opening new perspectives for novel deprogramming agents.

Congenital anomalies of inferior vena cava in young patients with iliac deep venous thrombosis.

Venous thromboembolism (VTE) in young patients is frequently associated with hereditary biological thrombophilia, autoimmune disorders, or neoplasia. Advances in venous ultrasound and contrast-enhanced computed tomography have allowed for the identification of inferior vena cava (IVC) anomalies as newly considered etiologic factor. We present two cases of VTE in young patients: the first case involves left IVC in a 22-year-old man and the second involves IVC atresia in a 39-year-old man. IVC anomalies should be identified in young patients with spontaneous VTE involving the iliac veins because they are at a high risk for thrombotic recurrence and adaptation to long periods of antithrombotic therapy.