NOTCH3 as a modulator of vascular disease: a target in elastin deficiency and arterial pathologies

During blood vessel disease, vascular smooth muscle cell (VSMC) expansion and interaction with the matrix trigger changes in gene expression and phenotype. In this issue of the JCI, Dave et al. discover a signaling network that drives VSMC expansion and vascular obstruction caused by elastin insufficiency. Using a combination of gene-targeted mice, tissues and cells from patients with Williams-Beuren syndrome, and targeting of elastin in human VSMCs, the authors identified VSMC-derived NOTCH3 signaling as a critical mediator of aortic hypermuscularization and loss of vascular patency. NOTCH3-specific therapies or therapies that target downstream molecular pathways may provide opportunities to minimize VSMC growth and treat cardiovascular disease with minimal side effects

Building and growing a successful F/BEVAR program

As an emerging technology, fenestrated and branched endovascular aneurysm repair (F/BEVAR) shows tremendous promise for managing complex aortic disease. However, pathways for building and growing a clinical program capable of successfully performing these repairs remain ill-defined. Fundamental to the process of program building is determining a clear vision of what defines success for the group and organization. First steps include decisions about the scope of the program and involvement of the US Food and Drug Administration. These decisions are interrelated with decisions about the extent of aneurysms that a program will treat and the types of devices needed to do so. The required financial resources and organizational infrastructure must be considered, with a thoughtful approach to the feasibility of such a clinical program. As for any clinical program, growth requires a track record of good clinical outcomes, patient experiences, and referring physician experiences. We describe an overview of these general considerations, while recognizing that local factors may dictate the applicability or lack thereof

Results of repeated percutaneous interventions on failing arteriovenous fistulas and grafts and factors affecting outcomes

OBJECTIVE: Repeated percutaneous interventions on failing arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) for hemodialysis are common, but the outcomes are largely unknown. We sought to determine the results of the second percutaneous intervention on failing AVGs and AVFs and to identify factors associated with loss of patency. METHODS: For the purpose of this study, the second percutaneous intervention was identified as the index procedure. We reviewed the second percutaneous interventions on failing AVFs and AVGs at a single institution between 2007 and 2013. Patient comorbidities, graft or fistula configuration, lesion characteristics, and procedural characteristics of the intervention performed were analyzed with respect to technical success, primary patency, primary assisted patency, and secondary patency. Patency was defined per Society for Vascular Surgery recommended reporting standards and was determined from the time of the index procedure. Cox proportional hazards multivariable modeling was performed to identify independent determinants of loss of patency. RESULTS: Among 91 patients, 96 second-time percutaneous interventions were performed on 52 AVFs and 44 AVGs. Patients included 56% men and 44% women with a mean age of 64 +/- 17 years. The lesions intervened on were primarily located along the accessed portion of the outflow in AVFs and within the length of the graft and at the venous anastomosis in AVGs. Transluminal angioplasty alone was performed in 82 procedures (85%), and uncovered or covered stents were placed in 15 procedures (16%). Pharmacomechanical thrombectomy was performed in 32 patients (34%) and was more commonly performed in AVGs compared with AVFs (53% vs 17%; P = .0002). Technical success was achieved in 90 procedures (97%; n = 92). One-year primary patency, assisted primary patency, and secondary patency rates were 35%, 86%, and 86%, respectively. One-year primary patency did not differ between AVFs and AVGs, but secondary patency was lower for AVG in comparison to AVF (P = .04). On multivariable analysis, only the need for pharmacomechanical thrombectomy significantly predicted failure of primary patency (hazard ratio, 2.6; 95% confidence interval, 1.6-4.3). The presence of an AVG rather than an AVF independently predicted failure of secondary patency (hazard ratio, 2.9; 95% confidence interval, 1.0-8.2). CONCLUSIONS: The second percutaneous interventions on AVFs and AVGs are associated with excellent technical success but poor primary patency. The need for pharmacomechanical thrombectomy predicts the need for additional percutaneous intervention to maintain patency. With additional interventions, acceptable secondary patency out to 5 years can be achieved, although AVGs have inferior secondary patency to AVFs. To develop optimal practice management algorithms, the effectiveness of repeated percutaneous interventions for failing AVGs and AVFs vs creation of a new access should be further investigated

CT Angiogram Area Stenosis Calculations Overestimate the Degree of Carotid Stenosis Compared to NASCET Diameter Stenosis Calculations

OBJECTIVE: The degree of carotid artery stenosis, as calculated by catheter-based angiography using NASCET methodology, has been shown to predict stroke risk in several large randomized controlled trials. In the current era, patients are increasingly being evaluated with CT-angiography (CTA) prior to carotid artery revascularization, especially as transcarotid artery revascularization (TCAR) adoption grows. Interpretation of CTA for degree of carotid stenosis has not been standardized, with both NASCET methodology and area stenosis being used. We performed a single-institution, blinded, retrospective analysis of CTAs using both NASCET methodology and CT-derived area stenosis to assess concordance/discordance between the two methods when evaluating \u3e /=70% and \u3e /=80% stenosis. METHODS: The UMass Memorial Medical Center vascular lab database was queried for all carotid duplex ultrasounds performed from 2008-2017. The dataset was winnowed to patients with duplex-defined \u3e /=70% stenosis (defined as peak systolic velocity (PSV) \u3e /=125 cm/s and an internal carotid-to-common carotid (ICA:CCA) ratio \u3e /=4), and a correlative CTA performed \u3c 1 year from duplex. A blinded review of all correlative CTA, using centerline measurements on a 3D workstation (Aquarius iNtuition Viewer, Terarecon, Durham, NC) was performed to characterize the degree of carotid stenosis by NASCET methodology and by area stenosis. Patients were excluded if revascularization was performed between the two imaging studies. RESULTS: Of 37,204 carotid duplex ultrasounds reviewed (2008-2017), 3,480 arteries met criteria for duplex defined \u3e /=70% stenosis. A correlative CTA within 1 year of the duplex was identified in 460 arteries, of which 320 were adequate quality for blinded review. The median days between duplex and CTA was 9.5 days. Concordance between area and NASCET methodologies were poor for both \u3e /=70% (kappa = 0.32) and \u3e /=80% stenosis (kappa = 0.25). Of 247 arteries considered to have \u3e /=70% area stenosis, 127 (51.4%) were considered to have \u3e /=70% NASCET stenosis. Of 169 arteries considered to have \u3e /=80% area stenosis, 44 (26.0%) were considered to have \u3e /=80% NASCET stenosis. CONCLUSIONS: Area stenosis CTA calculations of carotid artery stenoses dramatically overestimate the degree of carotid stenosis compared to that calculated by NASCET methodology. Given that stroke risk estimates are based on trials that used NASCET methodology, area stenosis likely overestimates the risk of stroke. Therefore, area stenosis calculations may lead to unnecessary carotid revascularization procedures. This model highlights the need for standardized utilization of NASCET methodology when utilizing CTA as the imaging modality to determine threshold for carotid revascularization

Carotid Duplex Velocity Criteria Recommended by the Society of Radiologists in Ultrasound and Endorsed by the Intersocietal Accreditation Commission Lack Predictive Ability for Identifying High-Grade Carotid Artery Stenosis.

BACKGROUND: Carotid duplex is the first-line imaging modality for characterizing degree of carotid stenosis. The Intersocietal Accreditation Commission (IAC), in published guideline documents, has endorsed use of the Society of Radiologists in Ultrasound (SRU) criteria to characterize ≥70% stenosis: peak systolic velocity (PSV) ≥230 cm/s. We sought to perform a validation of the SRU criteria using computed tomography (CT) angiography as a gold standard imaging modality and to perform a sensitivity analysis to determine optimal velocity criteria for identifying ≥80% stenosis. METHODS: We queried all carotid duplex examinations performed at our institution between 2008 and 2017. Patients with ≥70% carotid stenosis, based on previous criteria, were identified. Of these patients, those who also had a CT angiogram of the neck within one year formed the study cohort. Patients who underwent carotid revascularization between the 2 imaging dates were excluded. Degree of stenosis, as reported from the CT angiogram, was considered the true degree of stenosis. Receiver operating characteristic (ROC) curves were generated to evaluate the SRU criteria and to identify the optimal discrimination threshold for high-grade carotid stenosis. RESULTS: Of 37,204 carotid duplex examinations, 3,478 arteries met criteria for ≥70% stenosis. Of these, 344 patients had a CT angiogram within 1 year of the carotid duplex (mean time between studies, 55 days, SD 6.5) and 240 (69.8%) were consistent with ≥80% carotid stenosis. The predictive ability of the SRU criteria to identify ≥70% stenosis was poor, with an area under the ROC curve (AUC) of 0.51. A sensitivity analysis to identify ≥80% stenosis demonstrated the optimal discrimination threshold to be PSV ≥450 cm/s or end diastolic velocity (EDV) ≥120 cm/s, with an AUC of 0.66. CONCLUSIONS: In this validation study, the SRU criteria, endorsed by the IAC, to identify ≥70% carotid stenosis had no predictive value. For detection of ≥80% stenosis, the optimal criteria are a PSV ≥450 cm/s or EDV ≥120 cm/s. This study demonstrates the critical importance of carotid duplex examination validation