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| 2. |
- Loth, Daan W, et al.
(author)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Journal article (peer-reviewed)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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| 3. |
- Paloschi, V., et al.
(author)
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Impaired splicing of fibronectin is associated with thoracic aortic aneurysm formation in patients with bicuspid aortic valve
- 2011
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In: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 31:3, s. 691-7
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients. METHODS AND RESULTS: The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (rho=0.58) but not in BAV (rho=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-beta treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-beta signaling pathway may explain the impaired EDA inclusion in BAV patients. CONCLUSIONS: Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.
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| 5. |
- Castaman, G., et al.
(author)
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Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study
- 2006
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In: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 4:10, s. 2164-2169
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Journal article (peer-reviewed)abstract
- Objectives: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). Patients and methods: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. Results: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. Conclusions: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases.
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| 6. |
- Maleki, S, et al.
(author)
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Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 35712-
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Journal article (peer-reviewed)abstract
- Individuals with a bicuspid aortic valve (BAV) are at significantly higher risk of developing aortic complications than individuals with tricuspid aortic valves (TAV) and defective signaling during the embryonic development and/or life time exposure to abnormal hemodynamic have been proposed as underlying factors. However, an explanation for the molecular mechanisms of aortopathy in BAV has not yet been provided. We combined proteomics, RNA analyses, immunohistochemistry, and electron microscopy to identify molecular differences in samples of non-dilated ascending aortas from BAV (N = 62) and TAV (N = 54) patients. Proteomic analysis was also performed for dilated aortas (N = 6 BAV and N = 5 TAV) to gain further insight into the aortopathy of BAV. Our results collectively showed the molecular signature of an endothelial/epithelial-mesenchymal (EndMT/EMT) transition-like process, associated with instability of intimal cell junctions and activation of RHOA pathway in the intima and media layers of ascending aorta in BAV patients. We propose that an improper regulation of EndMT/EMT during the spatiotemporally related embryogenesis of semilunar valves and ascending aorta in BAV individuals may result in aortic immaturity and instability prior to dilation. Exasperation of EndMT/EMT state in post embryonic life and/or exposure to non-physiological hemodynamic could lead to the aneurysm of ascending aorta in BAV individuals.
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| 8. |
- Clausen, Niels, et al.
(author)
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Similar bleeding phenotype in young children with haemophilia A or B : A cohort study
- 2014
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In: Haemophilia. - : Wiley. - 1351-8216. ; 20:6, s. 747-755
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Journal article (peer-reviewed)abstract
- The bleeding phenotype has been suggested to differ between haemophilia A and B. More knowledge on the bleeding phenotype at initiation of treatment is important to optimize patient care. The aim of this study was to investigate the severity of the bleeding phenotype and the variation in bleeding in children with severe or moderate haemophilia A and B. Consecutive, previously untreated patients with severe or moderate haemophilia A and B (factor VIII or IX activity <0.01 or 0.01-0.05 IU mL-1 respectively) born between January 1st 2000 and January 1st 2010 were included. Primary outcome was severity of bleeding tendency. Secondary outcome was variation in bleeding pattern. A total of 582 patients with severe haemophilia A and 76 with severe haemophilia B did not differ in age at first exposure to clotting factor (0.81 vs. 0.88 years, P = 0.20), age at first bleed (0.82 vs. 0.88 years, P = 0.36), and age at first joint bleed (1.18 vs. 1.20 years, P = 0.59). Patients with moderate haemophilia were older compared to patients with severe haemophilia. In patients with moderate haemophilia there were no clear differences between haemophilia A and B. Severity and variation in bleeding phenotype are similar during the early stage of treatment in patients with severe and moderate haemophilia A and B respectively. The findings imply that children with haemophilia B should be observed and treated as vigilantly as those with haemophilia A.
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| 9. |
- Jenner, J., et al.
(author)
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Pre- and postoperative left atrial and ventricular volumetric and deformation analyses in severe aortic regurgitation
- 2021
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In: Cardiovascular Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120. ; 19:1
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Journal article (peer-reviewed)abstract
- Background The impact of volume overload due to aortic regurgitation (AR) on systolic and diastolic left ventricular (LV) indices and left atrial remodeling is unclear. We assessed the structural and functional effects of severe AR on LV and left atrium before and after aortic valve replacement. Methods Patients with severe AR scheduled for aortic valve replacement (n = 65) underwent two- and three-dimensional echocardiography, including left atrial strain imaging, before and 1 year after surgery. A control group was selected, and comprised patients undergoing surgery for thoracic aortic aneurysm without aortic valve replacement (n = 20). Logistic regression analysis was used to assess predictors of impaired left ventricular functional and structural recovery, defined as a composite variable of diastolic dysfunction grade >= 2, EF < 50%, or left ventricular end-diastolic volume index above the gender-specific normal range. Results Diastolic dysfunction was present in 32% of patients with AR at baseline. Diastolic LV function indices and left atrial strain improved, and both left atrial and LV volumes decreased in the AR group following aortic valve replacement. Preoperative left atrial strain during the conduit phase added to left ventricular end-systolic volume index for the prediction of impaired LV functional and structural recovery after aortic valve replacement (model p < 0.001, accuracy 70%; addition of left atrial strain during the conduit phase to end-systolic volume index p = 0.006). Conclusions One-third of patients with severe AR had signs of diastolic dysfunction. Aortic valve surgery reduced LV and left atrial volumes and improved diastolic indices. Left atrial strain during the conduit phase added to the well-established left ventricular end-diastolic dimension for the prediction of impaired left ventricular functional and structural recovery at follow-up. However, long-term follow-up studies with hard endpoints are needed to assess the value of left atrial strain as predictor of myocardial recovery in aortic regurgitation.
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