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Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations.

ABSTRACT: Background Patients with hereditary hemorrhagic telangiectasia have liver vascular malformations that can cause high-output cardiac failure (HOCF). Known sequelae include pulmonary hypertension, tricuspid regurgitation, and atrial fibrillation. Methods and Results The objectives of this study were to describe the clinical, echocardiographic, and hemodynamic characteristics and prognosis of hereditary hemorrhagic telangiectasia patients with HOCF who were found to have a subaortic membrane (SAoM). A retrospective observational analysis comparing patients with and without SAoM was performed. Among a cohort of patients with HOCF, 9 were found to have a SAoM in the left ventricular outflow tract by echocardiography (all female, mean age 64.8±4.0 years). The SAoM was discrete and located in the left ventricular outflow tract 1.1±0.1 cm below the aortic annular plane. It caused turbulent flow, mild obstruction (peak velocity 2.8±0.2 m/s, peak gradient 32±4 mm Hg), and no more than mild aortic insufficiency. Patients with SAoM (n=9) had higher cardiac output (12.1±1.3 versus 9.3±0.7 L/min, P=0.04) and mean pulmonary artery pressures (36±3 versus 28±2 mm Hg, P=0.03) compared with those without SAoM (n=19) during right heart catheterization. Genetic analysis revealed activin receptor-like kinase 1 mutations in each of the 8 patients with SAoM who had available test results. The presence of a SAoM was associated with a trend towards higher 5-year mortality during follow-up. Conclusions SAoM with mild obstruction occurs in patients with hereditary hemorrhagic telangiectasia and HOCF. SAoM was associated with features of more advanced HOCF and poor outcomes.

SUBMITTER: Kim AS

PROVIDER: S-EPMC7763373 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations.

Kim Agnes S AS Henderson Katharine J KJ Pawar Sumeet S Kim Min Jung MJ Punjani Shahnaz S Pollak Jeffrey S JS Fahey John T JT Garcia-Tsao Guadalupe G Sugeng Lissa L Young Lawrence H LH

Journal of the American Heart Association 20201015 20

Background Patients with hereditary hemorrhagic telangiectasia have liver vascular malformations that can cause high-output cardiac failure (HOCF). Known sequelae include pulmonary hypertension, tricuspid regurgitation, and atrial fibrillation. Methods and Results The objectives of this study were to describe the clinical, echocardiographic, and hemodynamic characteristics and prognosis of hereditary hemorrhagic telangiectasia patients with HOCF who were found to have a subaortic membrane (SAoM) ...[more]

PMID: 33054561

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Project description:BackgroundHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.MethodsWe selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.ResultsThe proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).ConclusionsIn this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.

Project description:Background Embolization is the standard of care for treatment of pulmonary arteriovenous malformations (PAVMs). Persistence of PAVMs after embolization occurs for undefined reasons but may include inflammation related to smoking in dysregulated angiogenesis. Purpose To determine whether patients with hereditary hemorrhagic telangiectasia (HHT) who smoke tobacco are more prone to PAVM persistence after embolization. Materials and Methods Patients with HHT treated for PAVMs between January 2000 and August 2017 were retrospectively identified. Only PAVMs with no previous treatment and patients with both clinical and imaging follow-up were included. Age, sex, PAVM characteristics (size, complexity, and location), embolization material used, microcatheter type, smoking history, active tobacco use, and other risk factors for arterial disease were analyzed by using a multivariate Cox proportional hazards model to determine risk factors for persistence. Results Five-year persistence-free survival rates in nonsmokers, smokers of 1-20 pack-years, and smokers of more than 20 pack-years were 12.2%, 21.9%, and 37.4% respectively. Smokers with more than 20 pack-years relative to nonsmokers had greater risk of persistence after adjusting for arterial feeder size (hazard ratio, 3.8; 95% confidence interval [CI]: 1.5, 10.0; P = .007). Patients who reported active tobacco use at the time of PAVM embolization had a 5-year cumulative incidence of persistence of 26.3% compared with 13.5% in inactive smokers. After adjusting for arterial feeder size, the risk of persistence was greater in tobacco users versus inactive smokers at the time of treatment (hazard ratio, 2.4; 95% CI: 1.2, 4.7; P = .01). Conclusion Smoking is associated with pulmonary arteriovenous malformation persistence after embolization in patients with hereditary hemorrhagic telangiectasia. Online supplemental material is available for this article. See also the editorial by Trerotola and Pyeritz in this issue.

Project description:BackgroundPulmonary first pass filtration of particles marginally exceeding ?7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.Methodology497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.Principal findingsSixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41-63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7-27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p?=?0.039/p?=?0.021).SignificanceThese data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.

Dataset Information

Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations.

Publications

Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations.

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