A triad of double aortic arch, bicuspid valve, and aortic dilation: treat the right lesion!
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ABSTRACT:
SUBMITTER: Dirbach F
PROVIDER: S-EPMC10986397 | biostudies-literature | 2024 Apr
REPOSITORIES: biostudies-literature
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A triad of double aortic arch, bicuspid valve, and aortic dilation: treat the right lesion!
Dirbach Fabienne F Roy Christopher C Stuber Matthias M Rutz Tobias T
European heart journal. Case reports 20240326 4
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Project description:BackgroundBicuspid aortic valve (BAV) is the most common congenital heart anomaly and is prone to cause complications, such as valvular stenosis and thoracic aortic dilation. There is currently no reliable way to predict the progression rate to thoracic aortic aneurysm. Here, we aimed to characterize the proteomic landscape in the plasma of stenotic BAV patients and provide potential biomarkers to predict progressive aortic dilation.MethodsPlasma samples were obtained from 45 subjects (30 stenotic BAV patients and 15 healthy controls). All samples were properly prepared and analyzed using mass spectrometry (MS)-based label-free quantitative proteomics.ResultsA total of 748 plasma proteins had missingness <50%, and 193 (25.8%) were differentially expressed in the BAV patients. Functions regarding cell junction and actin cytoskeleton were largely enriched. NOTCH3, a Notch receptor known to interact with the BAV-causing gene NOTCH1, was negatively correlated with aortic diameter and was downregulated in BAV patients' plasma and aortic smooth muscle cells. Further, a subset of plasma proteins, including ADAM10, was associated with rapidly progressive aortic dilation in BAV patients.ConclusionsOur data reveal unique features in the proteomic architecture of stenotic BAV patients' plasma, and we propose the potential of Notch signaling proteins NOTCH3 and ADAM10 in predicting aortic dilation.
| S-EPMC8350663 | biostudies-literature
Project description:BackgroundBicuspid aortic valve (BAV), the most common congenital heart defect affecting 1% to 2% of the population, is a major risk factor for premature aortic valve disease and accounts for the majority of valve replacement. The genetic basis and mechanisms of BAV etiology and pathogenesis remain largely undefined.MethodsCardiac structure and function was assessed in mice lacking a Gata6 allele. Human GATA6 gene variants were analyzed in 452 BAV cases from the BAV consortium and 1849 controls from the Framingham GWAS (Genome Wide Association Study). GATA6 expression was determined in mice and human tissues using quantitative real-time polymerase chain reaction and immunohistochemistry. Mechanistic studies were carried out in cultured cells.ResultsGata6 heterozygous mice have highly penetrant right-left (RL)-type BAV, the most frequent type in humans. GATA6 transcript levels are lower in human BAV compared with normal tricuspid valves. Mechanistically, Gata6 haploinsufficiency disrupts valve remodeling and extracellular matrix composition through dysregulation of important signaling molecules, including matrix metalloproteinase 9. Cell-specific inactivation of Gata6 reveals an essential role for GATA6 in secondary heart field myocytes because loss of 1 Gata6 allele from Isl- 1-positive cells-but not from endothelial or neural crest cells-recapitulates the phenotype of Gata6 heterozygous mice.ConclusionsThe data identify a new cellular and molecular mechanism underlying BAV. The availability of an animal model for the most frequent human BAV opens the way for the elucidation of BAV pathogenesis and the development of much needed therapies.
| S-EPMC6151169 | biostudies-literature
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| S-EPMC8789732 | biostudies-literature
Project description:IntroductionArterial tortuosity has emerged as a predictor of adverse outcomes in congenital aortopathies using 3D reconstructed images. We validated a new method to estimate aortic arch tortuosity on 2D CT. We hypothesize that arch tortuosity may identify bicuspid aortic valve (BAV) patients at high risk to develop thoracic aortic aneurysms or aortic dissections (TAD).MethodsBAV subjects with chest CT scans were retrospectively identified in our clinical records and matched to tricuspid aortic valve (TAV) controls by age, gender, and presentation with TAD. Subjects with prior ascending aortic intervention were excluded. Measurements included aortic arch tortuosity, length, angle, width and height. Total aortic tortuosity was estimated in subjects with available abdominal images.Results120 BAV and 234 TAV subjects were included. Our 2D measurements were highly correlated with 3D midline arch measurements and had high inter- and intra-observer reliability. Compared to TAV, BAV subjects had increased arch tortuosity (median 1.76 [Q1-Q3: 1.62-1.95] vs. 1.63 [1.53-1.78], P < 0.01), length (149 [136-160] vs. 135 [122-152] mm, P < 0.01), height (46 [41-53] vs. 39 [34-47] mm, P < 0.01), and vertex acuity (70 [61-77] vs. 75 [68-81] degree, P < 0.01). In a multivariable analysis, arch tortuosity remained independently associated with BAV after adjusting for aortic diameter and other clinical characteristics.ConclusionsWe found that aortic arch tortuosity is significantly increased in BAV and may identify BAV patients who are at increased risk for TAD. Further studies to evaluate the association between tortuosity and clinical outcomes are in progress.
| S-EPMC6436988 | biostudies-literature
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| S-EPMC10236863 | biostudies-literature
Project description:BackgroundBicuspid aortic valves (BAV) are frequently associated with ascending aortic aneurysms. The etiology is incompletely understood, but genetic factors, in addition to flow perturbations, are likely involved. Since loss of contractility and elaboration of extracellular matrix in the vessel wall are features of BAV-associated aortopathy, phenotypic modulation of smooth muscle cells (SMCs) may play a role.MethodsAscending aortic tissue was collected intra-operatively from 25 individuals with normal (i.e., tricuspid) aortic valves (TAV) and from 25 individuals with BAVs. For both TAV and BAV, 10 patients had non-dilated (ND) and 15 patients had dilated (D) aortas. SMCs were isolated and cultured from a subset of patients from each group. Aortic tissue and SMCs were fluorescently immunolabeled for SMC phenotypic markers (i.e., alpha-smooth muscle actin (ASMA, contractile), vimentin (synthetic) and p16INK4a and p21Cip1 (senescence). SMCs were also analyzed for replicative senescence in culture.ResultsIn normal-sized and dilated BAV aortas, SMCs switched from the contractile state to either synthetic or senescent phenotypes, as observed by loss of ASMA (ND: P = 0.001, D: P = 0.002) and associated increases in vimentin (ND: P = 0.03, D: P = 0.004) or p16/p21 (ND: P = 0.03, D: P<0.0001) compared to TAV. Dilatation of the aorta exacerbated SMC phenotypic switching in both BAV and TAV aortas (all P<0.05). In SMCs cultured from normal and dilated aortas, those isolated from BAV reached replicative senescence faster than those from TAV aortas (all P = 0.02). Furthermore, there was a stark inverse correlation between ASMA and cell passage number in BAV SMCs (ND: P = 0.0006, D: P = 0.01), but not in TAV SMCs (ND: P = 0.93, D: P = 0.20).ConclusionsThe findings of this study provide direct evidence from cell culture studies implying that SMCs switch from the contractile state to either synthetic or senescent phenotypes in the non-dilated BAV aorta. In cultured SMCs from both non-dilated and dilated aortas, we found that this process may precede dilatation and accompany aneurysm development in BAV. Our findings suggest that therapeutically targeting SMC phenotypic modulation in BAV patients may be a viable option to prevent or delay ascending aortic aneurysm formation.
| S-EPMC11218944 | biostudies-literature
Project description:ObjectivesThe aim of this study was to evaluate the role of wall shear stress (WSS) as a predictor of ascending aorta (AAo) growth at 5 years or greater follow-up.BackgroundAortic 4-dimensional flow cardiac magnetic resonance (CMR) can quantify regions exposed to high WSS, a known stimulus for arterial wall dysfunction. However, its association with longitudinal changes in aortic dilation in patients with bicuspid aortic valve (BAV) is unknown.MethodsThis retrospective study identified 72 patients with BAV (age 45 ± 12 years) who underwent CMR for surveillance of aortic dilation at baseline and ≥5 years of follow-up. Four-dimensional flow CMR analysis included the calculation of WSS heat maps to compare regional WSS in individual patients with population averages of healthy age- and sex-matched subjects (database of 136 controls). The relative areas of the AAo and aorta (in %) exposed to elevated WSS (outside the 95% CI of healthy population averages) were quantified.ResultsAt a median follow-up duration of 6.0 years, the mean AAo growth rate was 0.24 ± 0.20 mm/y. The fraction of the AAo exposed to elevated WSS at baseline was increased for patients with higher growth rates (>0.24 mm/y, n = 32) compared with those with growth rates <0.24 mm/y (19.9% [IQR: 10.2%-25.5%] vs 5.7% [IQR: 1.5%-21.3%]; P = 0.008). Larger areas of elevated WSS in the AAo and entire aorta were associated with higher rates of AAo dilation >0.24 mm/y (odds ratio: 1.51; 95% CI: 1.05-2.17; P = 0.026 and odds ratio: 1.70; 95% CI: 1.01-3.15; P = 0.046, respectively).ConclusionsThe area of elevated AAo WSS as assessed by 4-dimensional flow CMR identified BAV patients with higher rates of aortic dilation and thus might determine which patients require closer follow-up.
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