mTOR pathway activation in large vessel vasculitis.

BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.

[Cardiac sarcoidosis: Diagnosis and therapeutic challenges]. / Sarcoïdose cardiaque : avancées diagnostiques et thérapeutiques.

Sarcoidosis is a granulomatous disorder of unknown cause characterized by non-caseating granuloma in young adults. Cardiac involvement is rare and range from 2 to 75% depending on diagnostic criteria. Cardiac involvement in sarcoidosis may be asymptomatic or may manifest as rhythm/conduction troubles or congestive heart failure. The diagnosis and treatment of cardiac sarcoidosis may be challenging. However, advances have come in recent years from the use of cardiac MRI and 18FDG-TEP scanner, as well as from the stratification of the risk of ventricular tachycardia/fibrillation. Due to the rarity of the disease, there is no reliable prospective large study to guide therapeutic strategy for cardiac sarcoidosis. Corticosteroids are probably efficacious, in particular in case of atrio-ventricular block or moderate heart failure. Immunosuppressive drugs have not been largely studied but methotrexate could be helpful. In refractory forms, TNF-α antagonists have been used with success.

Takayasu Arteritis and Pregnancy.

OBJECTIVE: To assess the relationship between Takayasu arteritis (TAK) and pregnancy outcome. METHODS: This study included 240 pregnancies in 96 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK and/or the 1994 Chapel Hill Consensus Conference nomenclature/criteria for vasculitis. We analyzed obstetric and maternal outcomes in women who were pregnant before and/or at the same time as or after TAK diagnosis. We assessed factors associated with complicated pregnancy. RESULTS: One hundred forty-two pregnancies occurred in 52 patients before TAK diagnosis (median age at pregnancy 26 years [interquartile range 23-30 years]), and 98 pregnancies occurred in 52 patients concomitant with or after TAK diagnosis (median age at pregnancy 28 years [interquartile range 26-31 years]). Pregnancies concomitant with or after TAK diagnosis had a 13-fold higher rate of obstetric complications compared to pregnancies before TAK diagnosis (odds ratio 13 [95% confidence interval 5-33], P < 0.0001). TAK was associated with a 40% frequency of obstetric complications, including preeclampsia/eclampsia (24 pregnancies [24%]), premature delivery (8 pregnancies [8%]), and intrauterine fetal growth restriction or death (5 pregnancies [5%]). Maternal complications of TAK occurred during 39% of pregnancies and included mainly new-onset or worsening hypertension (26 pregnancies [27%]). In multivariate analysis, smoking (odds ratio 6.15 [95% confidence interval 1.31-28.8]) and disease activity of TAK (a National Institutes of Health score of >1) (odds ratio 28.7 [95% confidence interval 7.89-104.7]) were independently associated with obstetric and maternal complications. CONCLUSION: TAK negatively affects pregnancy outcomes. Disease activity increases the risk of obstetric and maternal complications, mainly due to arterial hypertension.

Th1 and Th17 cytokines drive inflammation in Takayasu arteritis.

OBJECTIVE: Takayasu arteritis (TAK) is a large-vessel vasculitis that induces damage to the aorta and its branches. Glucocorticoids remain the gold standard of therapy for TAK. The nature of the T cells driving vascular inflammation and the effects of glucocorticoids on the systemic components of TAK are not understood. The aim of this study was to analyze T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta in patients with TAK. METHODS: T cell homeostasis and cytokine production in peripheral blood and inflammatory lesions of the aorta were analyzed using Luminex analysis, flow cytometry, and immunohistochemical analysis. The study included 41 patients fulfilling the American College of Rheumatology 1990 criteria for the classification of TAK (17 patients with active TAK and 24 patients with disease in remission), 30 patients with giant cell arteritis and 39 patients with Behçet's disease (disease controls), and 20 age- and sex-matched healthy control subjects. RESULTS: We observed a marked increase in the expression of Th1 and Th17 cells, which correlated with TAK disease activity. The addition of serum from patients with active TAK to sorted CD4+ T cells from healthy donors in culture medium induced significant production of interferon-γ (IFNγ) and interleukin-17A (IL-17A). We demonstrated the presence of IFNγ-, IL-6-, and IL-17A-producing T cells in vascular inflammatory infiltrates in patients with TAK. Corticosteroid therapy was associated with decreased levels of circulating Th1 cytokines in corticosteroid-treated patients with TAK compared with steroid-free patients with TAK (for IL-2, mean ± SD 5,079 ± 5,300 versus 7,359 ± 3,197 pg/ml; for IFNγ, 2,592 ± 3,072 versus 8,393 ± 3,392 pg/ml; for tumor necrosis factor α, 847 ± 724 versus 1,491 ± 392 pg/ml). However, glucocorticoids had essentially no effect on the frequency of Th17 cytokines (IL-1 receptor, IL-17, and IL-23). CONCLUSION: The Th17 and Th1 pathways contribute to the systemic and vascular manifestations of TAK. Glucocorticoid treatment suppresses Th1 cytokines but spares Th17 cytokines in patients with TAK.

Early-TIPSS placement prevents rebleeding in high-risk patients with variceal bleeding, without improving survival.

BACKGROUND: Early-TIPSS (transjugular intrahepatic portosystemic shunt) placement may improve rebleeding and reduce 1-year mortality, compared to standard management in high-risk patients with cirrhosis and variceal bleeding. AIM: To obtain external validation of this therapeutic approach. METHODS: We performed a prospective study including all consecutive patients with Child-Pugh C 10-13 cirrhosis or Child-Pugh B with active bleeding at endoscopy admitted to our ICU between March 2011 and February 2013 for variceal bleeding. TIPSS were placed within 72 h after stabilisation. Patients were matched for gender, age, Child-Pugh score, MELD score and to patients from a historical cohort hospitalised before March 2011. RESULTS: 31/128 patients with cirrhosis (77.4% men, mean age 53.2 ± 9.0 years old, MELD score 20.9 ± 6.9, Child-Pugh C: 77.4%) admitted for acute variceal bleeding between March 2011 and February 2013 (TIPSS+ group) were matched to 31 historical patients (TIPSS- group). Uncontrolled bleeding occurred in 1/31 patients in the TIPSS+ group vs. 2/31 patients in TIPSS- group (P = 0.55). The 1-year probability of being free of rebleeding was higher in the TIPSS+ group (97% vs. 51%, P < 0.001). Actuarial 1-year survival was not different between the two groups (66.8 ± 9.4% vs. 74.2 ± 7.8%, P = 0.78). Acute cardiac failure occurred more frequently in the TIPSS+ group (25.8% vs. 6.4%, P = 0.03). CONCLUSIONS: Early-TIPSS placement effectively prevents rebleeding in high-risk patients with variceal bleeding but does not significantly improve survival. This might be due to the high proportion of patients with Child-Pugh C cirrhosis in our series. Cardiac failure may play a role and must be investigated before the procedure, when possible.

Thoracic involvement in systemic primary vasculitis: radiological patterns and follow-up.

Systemic primary vasculitides are rare idiopathic diseases causing an inflammatory injury to the vessel walls. A pulmonary involvement is frequent, and chest-CT is the imaging technique of reference in its assessment. An extremely wide variety of parenchymal, vascular and airways abnormalities, has been described and diagnosis can be challenging: knowledge of clinical data and a close cooperation with the referring physician is often crucial. The aim of this work is to describe the most common typical and atypical CT features of pulmonary vasculitis and their possible changes over time and therapy, focusing on the differential diagnosis with other inflammatory/infectious or neoplastic diseases.

[Erdheim-Chester disease]. / Maladie d'Erdheim-Chester.

Erdheim-Chester disease is a rare and orphan disease. Despite having been overlooked previously, numerous new cases have been diagnosed more recently. The number of Erdheim-Chester disease cases reported has increased substantially: more than 300 new cases have been published in the past 10 years. This situation is mainly a result of the generally better awareness among pathologists, radiologists, and clinicians of various aspects of this rare disease. The field has been particularly active in the last few years, with evidence of the efficacy of interferon-α, the description of a systemic pro-inflammatory cytokine signature, and most recently, reports of the dramatic efficacy of BRAF inhibition in severe, BRAF(V600E) mutation-associated cases of Erdheim-Chester disease. Also, BRAF mutations have been found in more than half of the patients with Erdheim-Chester disease who were tested. Detailed elucidation of the pathogenesis of the disease is likely to lead to the development of better targeted and more effective therapies.

[Cardiovascular involvement in Behçet's disease]. / Atteintes cardiovasculaires de la maladie de Behçet.

Vascular involvement is a common complication of Behçet's disease (BD) and affects up to 40% of BD patients. These complications worsen the prognosis of BD. The concept of vasculo-Behçet has been adopted for cases in which vascular complications dominate the clinical features. Vascular manifestations affect particularly young men, during the first years following onset of the disease. Venous complications are the most frequent vascular complications, affecting 14 to 40% of BD patients. Superficial and deep lower limb thrombosis is the most frequent venous complications but one third of venous thrombosis concern large vessels (such as cerebral venous thrombosis, pulmonary embolism, and inferior or superior vena cava, etc.). Budd-Chiari syndrome is the worst prognostic factor increasing mortality by 9 times. Arterial complications (2 to 17% of BD patients) include aneurysms and occlusions/stenosis. Main locations of arterial lesions are aortic (abdominal and thoracic), femoral, pulmonary and iliac arteries. Aneurysms are the most severe arterial complications, particularly pulmonary aneurysms associated with a high risk of massive bleeding. Cardiac complications (up to 6% of BD patients) include pericarditis, endocardial lesions (aortic regurgitation and less often mitral insufficiency), myocardial lesions (myocardial infarction, myocarditis and endomyocardial fibrosis) and intracardiac thrombosis (right ventricle and atrium). Coronary lesions complicated to myocardial infarction are the most severe cardiac complications. Treatment is based on corticosteroids and immunosuppressive drugs. The use of anticoagulation in venous thrombosis is still controversial.

Influence of peripheral vascular calcification on efficiency of screening tests for peripheral arterial occlusive disease in diabetes--a cross-sectional study.

AIMS: Pulse palpation and ankle brachial index are recommended to screen for peripheral arterial occlusive disease in people with diabetes. However, vascular calcification can be associated with false negative tests (arteriopathy present despite normal screening tests). We therefore studied the impact of peripheral vascular calcification on the performance of these tests. METHODS: This cross-sectional study included 200 people with diabetes at high risk of cardiovascular disease. The main exclusion factor was an estimated glomerular filtration rate < 30 ml/min. Peripheral arterial occlusive disease was diagnosed by colour duplex ultrasonography and peripheral vascular calcification scored by computed tomography scan. We measured sensitivity, specificity, predictive values, accuracy and likelihood ratios of pulse palpation and ankle brachial index, and looked for the impact of calcification on false negative tests (arteriopathy present despite normal screening tests). RESULTS: Ankle brachial index alone had poor sensitivity and negative predictive value and high negative likelihood ratio. Pulse palpation had higher sensitivity and negative predictive value. An abnormal pulse palpation, defined by weak or missing pulses, combined with an abnormal ankle brachial index, had the highest sensitivity and negative predictive value (92.3 and 89.8%, respectively). Vascular calcification score was higher in patients with false negative tests, for both pulse palpation and ankle brachial index (P < 0.0001 for all). Ankle systolic blood pressure was higher in patients with false negative tests for pulse palpation (P = 0.004). CONCLUSIONS: Below-knee vascular calcification gave a high rate of false negative results for ankle brachial index. Refined pulse palpation combined with ankle brachial index remained the best strategy to screen for peripheral arteriopathy.

Comparison of various methods for quantitative evaluation of myocardial infarct volume from magnetic resonance delayed enhancement data.

BACKGROUND: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) enables the estimation of myocardial infarct (MI) extent. Nevertheless, manual quantification is time consuming and subjective. We sought to assess MI volume with different quantitative methods in both acute (AMI) and chronic MI (CMI). METHODS: CMR was performed 50 ± 21 h after MI in 52 patients and was repeated 100 ± 21 days later in a subgroup of 34 patients. Then, necrosis volumes were quantified using: 1) manual delineation, 2) automated fuzzy c-means method, and 3) +2 to 6 SD thresholding approaches. Results were compared against peak values of serum Troponin I (TnI), creatine kinase (CK) and left ventricular (LV) functional parameters: LV ejection fraction (LVEF), indexed end-diastolic (EDVi), end-systolic volumes (ESVi) and the number of hypokinetic segments (NbHk). RESULTS: For CMI, quantitative evaluation of infarct size using manual, +2SD, +3 SD and fuzzy c-means provided equivalent results in terms of correlation coefficients for comparisons of MI volumes against LV function parameters (LVEF: r>0.79, p<0.0001; ESVi: r>0.82, p<0.0001, EDVi: r>0.67, p<0.0001, NbHk: r>0.54, p<0.0009). For AMI, +2SD and fuzzy c-means approaches provided higher correlations for comparisons of AMI volumes against biochemical markers (CK: r>0.79, p<0.0001,TnI: r>0.77, p<0.0001) and chronic LV function parameters (LVEF: r>0.82, p<0.0001, NbHk: r>0.59, p<0.0002). CONCLUSIONS: The fuzzy c-means and 2SD methods provided highest correlations with biochemical MI quantification as well as LV function parameters. The fuzzy c-means approach which does not require an arbitrary identification of the remote myocardium is fast and reproducible. It may be clinically useful in the evaluation of patients with MI.

Dilated cardiomyopathy in patients with mutations in anoctamin 5.

BACKGROUND: Homozygous mutations in ANO5, a gene encoding anoctamin 5, a putative calcium-activated chloride channel, have recently been reported in patients with adult-onset myopathies or isolated high-CK levels. Cardiomyopathy has not previously been reported in these populations despite a proven expression of anoctamin 5 in the cardiac muscle. METHODS: Patients presenting for the management of high-CK levels or overt myopathy with proven ANO5 mutations were prospectively investigated between June 2010 and March 2012 in Pitié Salpêtrière Hospital, according to a standardised protocol. Neurological and cardiological clinical examinations, CK assessment, electrocardiogram (ECG), and echocardiography were performed, as well as cardiac MRI and coronary CT angiography in patients with left ventricular (LV) dysfunction. RESULTS: Our study included 19 consecutive patients (male=15, age=46.2 ± 12.7 years) from 16 families. Five had asymptomatic high-CK levels and 14 had overt myopathy. One patient had a personal history of stable coronary artery disease with normal ventricular function. ECG showed ventricular premature beats in one patient. Echocardiography displayed LV dilatation in two patients, LV dysfunction in one, and both abnormalities in two who fulfilled criteria for dilated cardiomyopathy which was confirmed by cardiac MRI and normal CT angiography. CONCLUSIONS: Dilated cardiomyopathy is a potential complication in patients with myopathies due to mutations in the ANO5 gene whose screening requires specific procedures.

How does the patho-physiology influence the treatment of pelvic congestion syndrome and is the result long-lasting?

The objectives of this study are to consider the influence of pathophysiology in the treatment of pelvic congestion syndrome (PCS) and to determine the criteria which impact on the long-term results. A classification of venous pathology including three types of pathophysiological conditions, independent of the location of the pelvic venous pathology, is developed and illustrated. These types, diagnosed by cross-sectional imaging and confirmed by phlebography, are associated with a specific therapeutic plan. The long-term results are dependent on the quality of the initial phlebographic mapping that must be selective and complete, the angiographic findings, in particular the study of collaterals feeding the venous anomalies, the treatment of all venous anomalies, the respect of contraindications, the use of appropriate materials and the occurrence of new pregnancies. In conclusion, the feasibility and satisfactory short-term results of endovascular treatment of PCS are admitted. Questions remain regarding the effectiveness of the different embolic agents and the long-term results of this treatment.

[Technological advances in cardiac CT]. / Evolutions technologiques en tomodensitométrie cardiaque.

The SFR-SFC presents guidelines dedicated to cardiac and coronary imaging using CT in the area of indications, technological requirement including both hardware and software, patient conditioning, CT protocols and related results concerning radiation dose, image quality and diagnostic value. These guidelines are based either on up-dated medical literature proofs and/or on expert consensus.

Endovascular treatment of descending aortic dissection (type B): short- and medium-term results.

BACKGROUND: Optimal treatment of type B dissections is open to debate. The use of endoprostheses is an option that requires evaluation. AIM: To report our experience with endoprostheses in type B aortic dissections. METHODS: We report our short- and medium-term results with covered prostheses for the treatment of acute (n=7) and chronic (n=28) type B aortic dissections. The criteria used to indicate treatment were the same as those usually used for surgery: acute complications or dilated aneurysm. Cover of the main intimal tear was obtained in all cases with an improvement in symptoms in patients with acute dissections. RESULTS: Early mortality was 14.3% (five patients), linked in three cases to the occurrence of a retrograde dissection of the ascending aorta. No neurological complications were observed. Four patients required an additional endovascular and/or surgical procedure. On early control scans, complete thrombosis of the false lumen at the thoracic level was observed in 40% of cases, partial thrombosis in 42.8% and an absence of thrombosis in 11.4%. After a mean follow-up of 20.8 months, one patient died of a pneumopathy. No secondary aneurysm expansion was noted at the thoracic stage whereas three patients presented with dilation of the abdominal aorta. CONCLUSION: The results of treatment of type B dissections with covered endoprostheses are encouraging. However, the morbimortality associated with treatment and the uncertainty of long-term results do not allow the use of this therapeutic option outside the criteria usually recognized to indicate surgery.

[Evolution of the treatment of chronic post-traumatic aneurysms of the descending thoracic aorta: 30 years experience]. / Evolution du traitement des anévrismes post-traumatiques chroniques de l'aorte thoracique descendante: une expérience personnelle de 30 ans.

The authors present the early and late results of a series of 40 patients treated for chronic post-traumatic aneurysms of the descending thoracic aorta from 1975 to 2005. With the exception of a patient who died of an intra-pleural rupture before surgery, the patients were treated by aortotomy and prosthetic graft (N=17), aortotomy and direct suture (N=17) or endoprosthesis (N=5). The use of distal aortic perfusion in 22 patients enabled 17 direct sutures (77.3%) thanks to extensive mobilisation of the aortic arch. Endoprostheses have been used since 1997 in high surgical risk patients with severe comorbid conditions. There were no deaths, one transient paraparesia after simple aortic clamping, one reoperation for a haemothorax and four cases of dysphonia due to paralysis of the recurrent laryngeal nerve. Thirty-five patients (90%) were followed up for an average of 119.7 +/- 16.4 months. There were no clinical complications and the late morphological results were good in all cases with the exception of one type 1 endoprosthetic leak. The treatment of chronic post-traumatic aneurysms of the descending thoracic aorta gives excellent early and late results, justifying wide operative indications. The wish to avoid use of a prosthesis in young patients with a long life expectancy should give preference to conventional surgical techniques which, providing distal aortic perfusion is employed, allow direct suture of three quarters of cases. Endovascular treatment is reserved only for "poor surgical risks".