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Background Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. Objective The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. Methods/design This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). Discussion The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). Trial registration ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or \"PIKopathies,\" range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

Purpose We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10 . Methods We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF. Results Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling. Conclusion Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

Abstract BACKGROUND Pial arterial supplies are sometimes found in patients with dural arteriovenous fistulas (DAVFs), though their characteristics have rarely been clarified. OBJECTIVE To investigate the characteristics of pial arterial supplies in DAVFs and to discuss their pathophysiology and treatment. METHODS Two hundred four consecutive patients with intracranial DAVFs over 11 yr were retrospectively reviewed. Clinical factors and radiological findings, including the presence of pial arterial supplies, were evaluated. Supply from a pial artery was classified into 2 categories: dilated pre-existing dural branches of pial arteries, and a “pure” pial supply. RESULTS Twenty-three of 204 patients (11.3%) showed an additional pial arterial supply. Multivariate analysis identified 3 independent predictors of a pial arterial supply: younger age (P < .0005), DAVF within the tentorium (P = .0162), and presence of venous dilatation (P = .0001). A dilated pre-existing dural branch of a pial artery was identified in 17 patients, while 8 had a pure pial supply. Of these 23 patients, 17 underwent interventional therapy. No postoperative intracranial hemorrhage or infarction occurred in patients with pial arterial supplies. CONCLUSION An additional pial supply is not uncommon in DAVFs and may be explained by a rich physiological pial arterial supply to the dura mater from the posterior circulation, while potential angiogenesis due to venous hypertension remains speculative. Prior to interventional treatment for DAVFs, recognition of a pial arterial supply to the DAVF might influence the treatment strategy and could help avoid inadvertent retrograde embolization of brain supplying vessels through the pial network.

Abstract BACKGROUND: High-grade dural arteriovenous fistulas (dAVFs) can present shunts with very different angio-architectural characteristics. Specific hemodynamic factors may affect clinical history and determine very different clinical courses. OBJECTIVES: To evaluate the relationship between some venous angio-architectural features in high-grade dAVFs and clinical presentation. Specific indicators of moderate or severe venous hypertension were analyzed, such as altered configurations of the dural sinuses (by a single or a dual thrombosis), or overload of cortical vessels (restrictions of outflow, pseudophlebitic cortical vessels, and venous aneurysms). METHODS: The institutional series was retrospectively reviewed (49 cases), and the pattern of venous drainage was analyzed in relationship with clinical presentation (benign/aggressive/hemorrhage). RESULTS: Thirty-five of 49 cases displayed cortical reflux (high-grade dAVFs). This subgroup displayed a benign presentation in 31.42% of cases, an aggressive in 31.42%, and hemorrhage in 37.14%. CONCLUSIONS: Our data confirm that within high-grade dAVFs, 2 distinct subpopulations exist according to severity of clinical presentation. Some indicators we examined showed correlation with aggressive nonhemorrhagic manifestations (outflow restriction and pseudophlebitic cortical vessels), while other showed a correlation with hemorrhage (dual thrombosis and venous aneurysms). Current classifications appear insufficient to identify a wide range of conditions that ultimately determine the organization of the cortical venous drainage. Intermediate degrees of venous congestion correlate better with the clinical risk than the simple definition of cortical reflux. The angiographic aspects of venous drainage presented in this study may prove useful to assess dAVF hemodynamic characteristics and identify conditions at higher clinical risk.

Background and Purpose: Dural arteriovenous fistulas (DAVF) can affect a variety of cerebral venous structures and can present at various clinical stages. This study was designed to introduce the characteristic manifestation of DAVF detected with both carotid and transcranial color-coded duplex ultrasonography (CDUS) and to evaluate the diagnostic value of CDUS in DAVF. Methods: Nineteen patients with DAVF confirmed by cerebral angiography were studied with CDUS. The sonogram and spectrum of the affected area were observed. Hemodynamic parameters such as peak systolic velocity, end-diastolic velocity, mean velocity and resistance index (RI) were measured and recorded in the feeding artery, draining vein and extracranial artery. All results were compared with cerebral angiography. Fifty healthy volunteers were enrolled as a control group. Related hemodynamic changes were compared between the patients and normal controls. Results: The blood flow of fistulas presented as an irregular mosaic color bolus with a clear boundary detected with CDUS. Blood flow imaging of fistulas was abnormal in 12 cases and absent in 7 cases. The detection rate was 63% (12/19). Fifty-three main feeding arteries (73.6%) were detected by ultrasonography. All the venous drainages through the transverse sinus and superior ophthalmic vein were detected, while the ones through the superior sagittal sinus and cortical vein were not. There was a significant difference in average diameter, flow velocity and RI of the occipital artery and superficial temporal artery between the patients and normal controls (p < 0.05). Conclusions: CDUS could indicate DAVF by analyzing both imaging results of the diseased region and hemodynamic changes of the relative vasculature. It is a promising technique for the diagnosis and follow-up study of DAVF.

A contralateral persistent superior vena cava (PSVC) can occur in a normal child or in association with congenital heart defects (CHDs). Its prevalence has been demonstrated in relatively small cohorts. We aim to assess the frequency of a PSVC in a large cohort of children with and without CHDs. To estimate its significance, we have searched for a PSVC in all children referred for echocardiography in our institution during a 16.5-year period. A group of 17,219 children comprised 8,140 children with a structural heart anomaly and 9,079 children with a structurally normal heart. Association between a PSVC and specific classes of CHD were looked for. A total of 288 children (1.7%) had a PSVC; 0.56% (51 of 9,079) in the normal heart group and 2.9% (237 of 8,140) in the congenital heart anomalies group. Odds ratio for having heart anomaly in the presence of PSVC was 5.2 (95% confidence interval 3.7 to 7.0). A PSVC was above all associated with atrioventricular septal defects, conotruncal malformations, and left-sided defects. The odds ratio of having PSVC in the aforementioned malformations compared with the normal heart group was 23.8, 13.6, and 11.0, respectively. In conclusion, although present in normal subjects, PSVC was more often associated with congenital heart and other anomalies, especially with atrioventricular septal defects, conotruncal malformations, and left-sided defects.

The superficial femoral artery (SFA) is a typical atherosclerosis-prone site. We aimed to explore whether the tortuosity of the SFA associates with the occurrence of atherosclerosis and investigate how vascular tortuosity influences the characteristics of blood flow. Ten patients diagnosed with atherosclerotic disease in their SFAs while free of systemic atherosclerosis risk factors were enrolled together with ten atherosclerosis-free patients. The tortuosity of each SFA was quantitatively evaluated by calculating the averaged curvature (AC), maximum curvature (MC) and fraction of high curvature (FC) based on the geometrical model reconstructed from medical images. Hemodynamic studies were performed using both geometrically simplified and anatomically realistic models of the SFA to systematically address the hemodynamic effects of vascular tortuosity. Morphological analyses revealed that all curvature indices of the SFA were significantly larger in patients with atherosclerosis than in atherosclerosis-free patients (AC [mm−1]: 0.034 ± 0.016 vs. 0.018 ± 0.006; MC [mm−1]: 0.055 ± 0.023 vs. 0.034 ± 0.008; FC [%]: 22.77 ± 10.22 vs. 11.39 ± 6.82; p < 0.001). Simulations of blood flows in the geometrically simplified SFAs showed that increasing vascular curvature caused a progressive increase in the area ratios of low wall shear stress (LWSA) and high oscillatory shear index (HOSA). Hemodynamic studies on the anatomically realistic SFAs further demonstrated that high-curvature SFAs (n = 10) had overall larger LWSA and HOSA compared with low-curvature SFAs (n = 10) (LWSA [%]: 4.13 ± 1.91 vs. 1.79 ± 1.13, p = 0.009; HOSA [%]: 4.95 ± 1.92 vs. 2.37 ± 1.51, p = 0.007). These results suggest that increased vascular tortuosity augments the severity and distribution of atherosclerosis-promoting flow disturbances in the SFA and may be an independent risk factor for atherosclerosis.

The population-based \"Asymptomatic Polyvascular Abnormalities in Community (APAC) Study was designed to examine prevalence and associations of asymptomatic polyvascular abnormalities (APA) in a general population. In this report, the objectives, design and baseline data of the APAC study are described. The study included 5,440 participants (40.1% women) with an age of 40+ years who were randomly selected from the population of the Kailuan Study which included 101,510 employees and retirees of the Kailuan Co. Ltd, a large coal mine industry located in Tangshan, Hebei, China. Exclusion criteria were previous cerebral stroke, transient ischemic attacks and coronary heart disease. In 2010 and 2011, information on potential cardiovascular risk factors was collected and all participants underwent transcranial Doppler sonography, measurement of the ankle brachial index, and bilateral carotid duplex sonography. In a first follow-up examination in 2012/2013, retinal photography and spectral-domain optical coherence tomography were additionally performed. In a planned long-term follow-up, data from clinical examinations and laboratory tests and the occurrence of cardiovascular or cerebrovascular events will be collected to build up a predicting model for the risk of ischemic events. At baseline, mean age of the participants was 55.2 ± 11.8 years, and men showed a significantly (P<0.001) higher prevalence of arterial hypertension (55.5% vs. 36.5%) and hyperlipidemia (50.7% vs. 46.0%) and a higher blood homocysteine concentration (18.68 ± 10.28 µmol/L versus 11.69 ± 6.40 µmol/L). The APAC is the first study to prospectively evaluate the relationship between intracranial arterial stenosis, retinal nerve fiber layer changes, retinal microvascular signs, and the eventual development of cerebrovascular or cardiovascular events.

Background Hereditary hemorrhagic telangiectasia (HHT) is characterized by telangiectasia and larger vascular malformations. Liver malformations are the most frequent visceral involvement including the presence of portosystemic malformations (PSM) that can cause hepatic encephalopathy. Minimal hepatic encephalopathy (mHE) is characterized by alterations of brain function in neuropsychological or neurophysiological tests and decreases quality of life. The evidence of mHE in HHT patients is scarce. The aim of this study is to assess the prevalence and health impact of mHE in patients with and without PSM. Methods We performed a cross-sectional observational study in a cohort of patients from an HHT referral unit. Adult patients with definite HHT and PSM and age and sex matched HHT controls without PSM (1:1) were included. Baseline clinical, imaging and laboratory tests and different neuropsychological tests for the screening of mHE were compared between both groups. Results Eighteen patients with PSM and 18 controls out of 430 HHT patients were included. Patients with PSM showed higher prevalence of attention disturbances (50% vs. 11.1%, p  = 0.027), falls during last 12 months (22.2% vs. 5.6%, p  = 0.338), sleep disorders (50% vs. 16.7%, p  = 0.075) and a worst performance in s-ANT1 test (14 vs. 19.5 points score, p  = 0.739) than HHT controls. Conclusions HHT patients with PSM showed higher attention difficulties than HHT controls, though both PSM and HHT controls showed findings of mHE. Specific neuropsychological tests for early detection of mHE should be considered in HHT patients.