Background:
Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the
FBN1
gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm (TAA). To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.
Methods:
Combining transcriptomics and metabolic analysis of aortas from a Marfan mouse model (
Fbn1
c1039g/+
) and MFS-patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMCs) by conditional depleting mitochondrial transcription factor A (Tfam) (
Myh11-Cre
ERT2
Tfam
flox/flox
mice). We have used a mouse model of Marfan syndrome to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration
Results:
The main canonical pathways highlighted in the transcriptomic analysis in aortas from
Fbn1
c1039g/+
mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial-DNA content, were reduced in aortas from young
Fbn1
c1039g/+
mice.
In vitro
experiments in
Fbn1
-silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS-patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient-VSMCs mice, lose their contractile capacity, showed aortic aneurysms and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside (NR) rapidly reverses aortic aneurysm in
Fbn1
c1039g/+
mice.
Conclusions:
Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan Syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
Non-aneurysmal SAH with a perimesencephalic pattern of bleeding has a benign course and excellent short-term and long-term prognosis. Patients with non-aneurysmal SAH with an aneurysmal pattern of bleeding have more complications, and the initial clinical situation has a significant impact on their prognosis.
The Pipeline Flex embolization device allows more precise and controlled deployment than the first-generation device. The number of devices and the complication rate during the learning curve are lower than reported with the first-generation PED. The new delivery system and the resheathing maneuvers do not seem to increase the intraprocedural complication rate in comparison with the first-generation PED.
In stroke secondary to cardiac myxoma, mechanical thrombectomy might represent a safe and effective treatment option. The authors suggest the use of histological examination of the clot for diagnosis as its composition may explain the differences in treatment outcome.
BACKGROUND AND PURPOSE: Radiation exposure from neurointerventional procedures can be substantial, with risk of radiation injuries. We present the results of a follow-up program applied to potential skin injuries in interventional neuroradiology based on North American and European guidelines.
Introduction: To assess the cost-effectiveness of stent-retriever mechanical thrombectomy and intravenous tissue plasminogen activator compared with intravenous tissue plasminogen activator alone in patients with acute ischaemic stroke due to large vessel occlusions in Spain. Materials and methods: Clinical data were taken from the SWIFT PRIME clinical trial. A lifetime Markov state transition model defined by the modified Rankin Scale score was developed to estimate costs and health outcomes (life years gained and quality adjusted life years). A Spanish National Health System perspective (direct medical costs) was considered. Resource utilisation and utilities were obtained from available published data and endorsed by an expert panel. Costs (E, 2016) were obtained from various Spanish sources. Deterministic and probabilistic sensitivity analyses were performed. Results: Stent-retriever thrombectomy after intravenous tissue plasminogen activator was associated with better outcomes (1.17 life years gained and 2.51 quality adjusted life years) and savings of E44,378, resulting in a dominant therapy over intravenous tissue plasminogen activator alone. A net monetary benefit of E119,744 was obtained considering a willingness-to-pay threshold of E30,000/quality adjusted life year gained. The combined therapy was also dominant in all sensitivity analyses, deterministic and probabilistic. Discussion: The results were consistent with a previously published cost-effectiveness analysis and reinforce the likeliness of the selection of stent-retriever mechanical thrombectomy plus intravenous tissue plasminogen activator over intravenous tissue plasminogen activator alone. Conclusion: Stent-retriever thrombectomy after intravenous tissue plasminogen activator is a dominant alternative over intravenous tissue plasminogen activator alone (more effective and less costly) for the treatment of acute ischaemic stroke patients with large vessel occlusions in the Spanish setting.
The Pipeline Flex device allows more precise and controlled deployment than the current PED device. Although this preliminary experience seems positive, multicenter larger series will be needed to confirm the safety and durability of this new device.
PurposeTo describe the efficacy and complications of treating cerebral aneurysms with the Flow Re-direction Endoluminal Device (FRED) and to identify predictors for aneurysm occlusion.MethodsA prospective observational registry including all consecutive aneurysms treated with FRED between December 2015 and July 2018 was designed in one therapeutic neuroangiography department. The primary endpoint for treatment efficacy was complete or near-complete occlusion (O’Kelly–Marotta (OKM) C–D), assessed by three-dimensional digital subtraction angiography. Major (all symptomatics) and minor complications were described and those with modified Rankin Scale scores 3–6 were considered clinically relevant. Univariate and multivariate analyses were performed to identify predictors of efficacy.ResultsA total of 185 aneurysms were analyzed in 150 patients (mean age 54.3±11.5 years). Mean follow-up was 18.99±11.32 months (range 0–43). Efficacy was evaluated in 156 (84.32%) cases: 132 (84.6%) had OKM C–D occlusion, 31/47 (66%) within the first year and 101/109 (92.7%) later on. Major complications were observed in 12 (6.5%) cases: three strokes (one transient ischemic accident, two minor strokes), six intra-stent thrombosis, and three with bleeding, but only one (0.5%) was clinically relevant. Minor complications (all asymptomatic) were observed in 10 (5.4%) cases: three shortening/repositioning of stent; two arterial dissection, two arterial occlusion, and three intra-stent stenosis. Independent predictors of occlusion were immediate OKM grade B–C–D (OR 4.01, 95% CI 1.51 to 10.62), single aneurysm (OR 3.29, 95% CI 1.05 to 10.32), and small size aneurysm (OR 4.74, 95% CI 1.57 to 14.30).ConclusionThe FRED stent fully complied with efficacy and safety requirements for treatment of intracranial aneurysms. Three predictors of aneurysm occlusion were identified.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.