Frank Hammer

Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast‐flow vascular anomalies are caused by RASA1 mutations

Capillary malformation‐arteriovenous malformation (CM‐AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one‐third had fast‐flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast‐flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM‐AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity. Hum Mutat 29(7), 959–965, 2008.

RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation

Capillary malformation–arteriovenous malformation (CM–AVM) is an autosomal‐dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast‐flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM–AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM–AVM (n = 100), common CM(s) (port‐wine stain; n = 100), Sturge–Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty‐eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM–AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the “second‐hit” hypothesis as a pathophysiological mechanism for CM–AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild‐type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM–AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast‐flow lesions warrants careful clinical and radiologic examination, and regular follow‐up.

Subclinical deep venous thrombosis observed in 10% of hemophilic patients undergoing major orthopedic surgery

To cite this article: Hermans C, Hammer F, Lobet S, Lambert C. Subclinical deep venous thrombosis observed in 10% of hemophilic patients undergoing major orthopedic surgery. J Thromb Haemost 2010; 8: 1138–40. Deep venous thrombosis (DVT) is a common postoperative complication in patients undergoing major orthopedic surgery of the lower limbs, such as total hip replacement (THR), total knee replacement (TKR) or hip fracture surgery (HFS). In the absence of thromboprophylaxis, subclinical venous thrombosis rates as high as 60% have been reported when using systematic bilateral phlebography after orthopedic surgery. As a result, routine pharmacological thromboprophylaxis with low-molecular-weight heparin (LMWH) or an alternative antithrombotic agent is strongly recommended in patients undergoing these procedures [1]. With the availability of efficient and safe clotting factor concentrates, THR, TKR as well as ankle arthrodesis are frequently performed in subjects with hemophilia suffering from chronic hemophilic arthropathy [2]. Yet, pharmacological prophylaxis of venous thromboembolism (VTE) in this patient group remains controversial. With the exception of retrospective case reports and small series, the incidence of VTE disease in hemophilic patients after major orthopedic surgery is still unclear. Despite the concern that pharmacological thromboprophylaxis might increase bleeding complications in these patients, no properly sized study has objectively evaluated the need, appropriate timing, dosage and duration of low-molecular weight heparin (LMWH) prophylaxis in this

Rationale and design of the Investigator-Steered Project on Intravascular Renal Denervation for Management of Drug-Resistant Hypertension (INSPiRED) trial.

Abstract The SYMPLICITY studies showed that renal denervation (RDN) is feasible as novel treatment for resistant hypertension. However, RDN is a costly and invasive procedure, the long-term efficacy and safety of which has not yet been proven. Therefore, we designed the INSPiRED trial to compare the blood pressure lowering efficacy and safety of RDN vs usual medical therapy. INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert hypertension centres in Belgium. Eligible patients, aged 20–69 years old, have a 24-h ambulatory blood pressure of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTNTM, SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic blood pressure and in glomerular filtration rate as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. Follow-up will continue up to 36 months after randomization. INSPiRED is powered to demonstrate a 10-mmHg difference in systolic blood pressure between randomized groups with a two-sided p-value of 0.01 and 90% power. It will generate long-term efficacy and safety data, identify the subset of treatment-resistant hypertensive patients responsive to RDN, provide information on cost-effectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers. Trial registration: ClinicalTrials.gov identifier: NCT01505010.

Rapamycin as Novel Treatment for Refractory-to-Standard-Care Slow-Flow Vascular Malformations.

METHODS: Informed consent was obtained and approved by our ethical committee. The trial is registered under VASCA-LM at clinicaltrials.gov (NCT01811667). Eighteen patients aged from 3 to 64 years with refractory-to-standard-care LMs (n=6), VMs (n=7) and/or complex vascular anomalies (n=5) were enrolled. Clinical symptoms included: chronic daily debilitating pain (n=12), functional impairment (n=9), recurrent infections (n=5), daily gastrointestinal bleeding (n=4), and chronic ulceration with oozing and bleeding (n=2), despite several sessions of sclerotherapies and/or surgery. Patients were seen on a monthly basis by the plastic surgeon and the oncologist. Efficacy was evaluated by anamnesis of symptoms (functional, cosmetic and psychological), pain evolution (frequency and intensity), quality of life questionnaire, clinical parameters, photos of the visible clinical lesions and blood sampling. A global self-evaluation percentage of increase/decrease in quality of life (including social and physical function, vitality, and pain) was recorded at each follow-up as well as side effects. Volumetric MRI using ITK-SNAP software was performed before initiation and at a yearly base.

Delayed endovascular coil extrusion after embolisation for post-tonsillectomy haemorrhage: case report and literature review.

OBJECTIVEnTo report a rare case of delayed endovascular coil extrusion following embolisation of a lingual artery pseudoaneurysm.nnnCASE REPORTnA 23-year-old woman presented with dysphagia and odynophagia 11 months after having experienced massive post-tonsillectomy haemorrhage. At that time, the bleeding had been stopped by embolisation of a lingual artery pseudoaneurysm and the external carotid artery. Clinical examination at admission showed extrusion of the embolisation coils in the lateral lower pharyngeal wall. The coils were removed under general anaesthesia in the presence of an interventional radiologist. The procedure and post-operative period were without complication and no bleeding was observed. The dysphagia and pain disappeared and the subsequent seven-month follow-up period was uneventful.nnnCONCLUSIONnAlthough selective embolisation is a safe and effective treatment for severe post-tonsillectomy haemorrhage, the possibility of delayed coil extrusion should be kept in mind.

Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension

Abstract Objective: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. Methods: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment withu2009≥3 drugs, of whom 17 after optimization of treatment (ageu2009<70 years; systolic/diastolic office blood pressure (BP)u2009≥u2009140/90u2009mm Hg; 24-h BPu2009≥130/80u2009mm Hg; glomerular filtration rate [eGFR]u2009≥u200945u2009mL/min/1.73 m2; body mass indexu2009<40kg/m2) were randomized and 15 were analyzed 6 months later, while medical treatment was continued (nu2009=u20099) or combined with RDN by the EnligHTN™ multi-electrode system (nu2009=u20096). Results: The baseline-adjusted between-group differences amounted to 19.5/10.4u2009mm Hg (change in control vs. intervention group,u2009+7.6/+2.2 vs. −11.9/−8.2u2009mmu2009Hg; Pu2009=u2009.088) for office BP, 22.4/13.1u2009mmu2009Hg (+0.7/+0.3 vs. −21.7/−12.8; mm Hg; Pu2009≤u2009.049) for 24-h BP, the primary efficacy endpoint, and 2.5u2009mL/min/1.73 m2 (+1.5 vs. −1.1u2009mL/min/1.73 m2; Pu2009=u2009.86) for eGFR, the primary safety endpoint. At 6 month, ECG voltages and the number of prescribed drugs (Pu2009≤u2009.036) were lower in RDN patients, but quality of life and adherence, captured by questionnaire and urine analysis were similar in both groups. Changes in BP and adherence were unrelated. No major complications occurred. Conclusions: The INSPiRED pilot suggests that RDN with the EnligHTN™ system is effective and safe and generated insights useful for the design of future RDN trials.

Renal artery and parenchymal changes after renal denervation: assessment by magnetic resonance angiography

AbstractObjectivesRelatively little is known about the incidence of long-term renal damage after renal denervation (RDN), a potential new treatment for hypertension. In this study the incidence of renal artery and parenchymal changes, assessed with contrast-enhanced magnetic resonance angiography (MRA) after RDN, is investigated.MethodsThis study is an initiative of ENCOReD, a collaboration of hypertension expert centres. Patients in whom an MRA was performed before and after RDN were included. Scans were evaluated by two independent, blinded radiologists. Primary outcome was the change in renal artery morphology and parenchyma.ResultsMRAs from 96 patients were analysed. Before RDN, 41 renal anomalies were observed, of which 29 mostly mild renal artery stenoses. After a median time of 366xa0days post RDN, MRA showed a new stenosis (25–49% lumen reduction) in two patients and progression of pre-existing lumen reduction in a single patient. No other renal changes were observed and renal function remained stable.ConclusionsWe observed new or progressed renal artery stenosis in three out of 96 patients, after a median time of 12xa0months post RDN (3.1%). Procedural angiographies showed that ablations were applied near the observed stenosis in only one of the three patients.Key Points• The incidence of vascular changes 12xa0months post RDN was 3.1%.n • No renal vascular or parenchymal changes other than stenoses were observed.n • Ablations were applied near the stenosis in only one of three patients.

Superior vena cava stenosis in haemodialysis patients with a tunnelled cuffed catheter: prevalence and risk factors

BackgroundnAlthough superior vena cava (SVC) stenosis may be a life-threatening complication of haemodialysis (HD) catheters, its prevalence and risk factors in HD patients are unknown. Our aim was to assess the prevalence and risk factors for SVC stenosis in HD patients with a tunnelled cuffed catheter (TCC) and to describe its clinical presentation.nnnMethodsnIn this single-centre, retrospective cohort study, all in-centre chronic HD patients carrying a TCC (1 January 2008-31 December 2012) were included (nu2009=u2009117 patients, 214 TCC, 80u2009911 catheter-days). SVC stenosis was defined as a diameter reduction >50% on phlebography or computed tomography. Imaging was triggered by clinical SVC stenosis syndrome or vascular access (VA)-related concerns. We recorded demographics, conditions potentially influencing catheter permeability (medications, carriage of thoracic devices), number of TCCs, total duration of TCC carriage, previous arteriovenous VA and last (in use at time of stenosis detection) TCC details (location, diameter and length). VAs created while a TCC was still used were also recorded.nnnResultsnAn SVC stenosis was found in 11 patients (9.4%, 0.14/1000 catheter-days), which represents almost one-quarter of patients undergoing imaging, whatever the cause (11/45). Only two presented with clinically obvious SVC stenosis. The number of TCCs per patient was 2.64u2009±u20091.8 in the SVC stenosis group versus 1.75u2009±u20090.94 in the negative group (Pu2009=u20090.13). On multivariate analysis (Poisson), diabetes {incidence rate ratio [IRR] 4.63 [confidence interval (CI) 1.2-17.8]; Pu2009=u20090.02} and total duration of TCC carriage [IRR 1.47 (CI 1.2-1.8) per year; Pu2009=u20090.001] were associated with SVC stenosis, whereas age had a slightly protective effect [IRR 0.96 (CI 0.91-1.01); Pu2009=u20090.01]. Limitations are the retrospective design, detection and survivor bias.nnnConclusionnSVC stenosis is not a rare condition, is mostly asymptomatic in the absence of a peripheral VA, is strongly associated with diabetes and is promoted by long TCC carriage. Age is slightly protective.

Management of a Pregnant Woman With Fibromuscular Dysplasia.

A 39-year-old woman of Moroccan origin presented to the Cardiology Department with high blood pressure, with systolic blood pressure repeatedly measured at 170 mmu2009Hg in the office. She was 10 days pregnant. Her treatment included nebivolol 5 mg and barnidipine 10 mg.nnHer medical history included migraines, an early miscarriage in 2001, and a second pregnancy with delivery at 27 weeks for preeclampsia in December 2014. At post-partum, she had received amlodipine, and then bisoprolol at another hospital. In September 2015, she had consulted at a third hospital for persistent hypertension with moderate to high blood pressure (systolic blood pressure: 170–190 mmu2009Hg). Blood pressure was measured at 170/80 mmu2009Hg in the office. Cardiac test results were normal. The physician concluded that the patient experienced chronic, rather than pregnancy-related hypertension, and replaced bisoprolol 5 mg with nebivolol 5 mg; barnidipine 10 mg was maintained, and the patient was asked to adhere to the therapeutic regimen. Despite mentioning that the hypertension was likely essential, he ordered an etiologic work-up. Renal function was normal (plasma creatinine: 58 μmol/L; estimated glomerular filtration rate: 100 mL/min per 1.73 m2). Urinary analysis revealed a mildly increased proteinuria of one-half gram per 24 hours. Urinary metanephrines were in the normal range, and the renal duplex study suggested a differential diagnosis of right renal artery stenosis and an arterial loop.nnDr Micali: I would check the urinary sodium to confirm whether the patient is adhering to the hyposodic diet. This is one approach to check and determine whether the patient is consuming salt or not.nnProfessor Persu: Yes, I think this is a good point, but this patient is not very adherent, and we had instances where we did not succeed in obtaining 24-hour urine samples. Additionally, this was performed in another hospital. I do not have …