Device closure of pulmonary arteriovenous malformation using Amplatzer vascular plug II in hereditary hemorrhagic telangiectasia.
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ABSTRACT:
SUBMITTER: Rajesh GN
PROVIDER: S-EPMC4593798 | biostudies-other | 2015 Sep-Oct
REPOSITORIES: biostudies-other
Publications
Device closure of pulmonary arteriovenous malformation using Amplatzer vascular plug II in hereditary hemorrhagic telangiectasia.
Rajesh Gopalan Nair GN Sajeer Kalathingathodika K Nair Anishkumar A Haridasan Vellani V Sajeev Chakanalil Govindan CG Krishnan Mangalath Narayanan MN
Indian heart journal 20150804 5
Pulmonary arteriovenous malformations (AVM) are very rare and carry the risk of cerebral thrombo-embolism, brain abscess or pulmonary hemorrhage. The Amplatzer vascular plug II (AVP II) is a new device, used for embolization of the pulmonary AVMs. We report a case of pulmonary AVM successfully managed by using AVP II in a patient with hereditary hemorrhagic telangiectasia (HHT). ...[more]
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Project description:Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs).We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis.The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0-70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42-2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25-31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11-1.73%).Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically.
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Project description:Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM) than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl) mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl) mice: R26CreER (all cell types after tamoxifen treatment), SM22?-Cre (smooth muscle and endothelial cell) and LysM-Cre (lysozyme M-positive macrophage). An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that SM22?-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.
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Project description:Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that leads to abnormal connections between arteries and veins termed arteriovenous malformations (AVM). Mutations in TGF? pathway members ALK1, ENG and SMAD4 lead to HHT. However, a Smad4 mouse model of HHT does not currently exist. We aimed to create and characterize a Smad4 endothelial cell (EC)-specific, inducible knockout mouse (Smad4f/f;Cdh5-CreERT2) that could be used to study AVM development in HHT. We found that postnatal ablation of Smad4 caused various vascular defects, including the formation of distinct AVMs in the neonate retina. Our analyses demonstrated that increased EC proliferation and size, altered mural cell coverage and distorted artery-vein gene expression are associated with Smad4 deficiency in the vasculature. Furthermore, we show that depletion of Smad4 leads to decreased Vegfr2 expression, and concurrent loss of endothelial Smad4 and Vegfr2 in vivo leads to AVM enlargement. Our work provides a new model in which to study HHT-associated phenotypes and links the TGF? and VEGF signaling pathways in AVM pathogenesis.
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Project description:A man affected by hereditary hemorrhagic telangiectasia who had chronic severe hypoxemia is presented. This hypoxemia was synergistically caused by high-output heart failure due to severe hepatic shunts and multiple pulmonary arteriovenous shunts. The symptomatic combination is rare, and genetic testing showed a novel endoglin mutation. (Level of Difficulty: Advanced.).
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