Update in Biomolecular and Genetic Bases of Bicuspid Aortopathy.
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ABSTRACT:
SUBMITTER: Junco-Vicente A
PROVIDER: S-EPMC8198265 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe bicuspid aortic valve (BAV) is prone to ascending aortic dilatation (AAD) involving both the tubular segment and the aortic root. The genetic factor was proposed as one of the most important mechanisms for AAD. We hypothesized that the rare genetic variants mainly contribute to the pathogenesis of aortic roots in affected individuals.MethodsThe diameter of aortic root or ascending aorta ≥ 40 mm was counted as AAD. The targeted next-generation sequencing of 13 BAV-associated genes were performed on a continuous cohort of 96 unrelated BAV patients. The rare variants with allele frequency < 0.05% were selected and analyzed. Variants frequency was compared against the Exome aggregation consortium database. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics guidelines.ResultsA total of 27 rare nonsynonymous coding variants involving 9 genes were identified in 25 individuals. The burden analysis revealed that variants in GATA5, GATA6, and NOTCH1 were significantly associated with BAV. Eighty percent of the pathogenic variants were detected in root group. The detection rate of rare variants was higher in root dilatation group (71.4%) compared with normal aorta (29.0%) and tubular dilatation groups (29.6%) (P = 0.018). The rare variant was identified as the independent risk factor of root dilatation [P = 0.014, hazard ratio = 23.9, 95% confidence interval (1.9-302.9)].ConclusionsOur results presented a broad genetic spectrum in BAV patients. The rare variants of BAV genes contribute the most to the root phenotype among BAV patients.
| S-EPMC8404252 | biostudies-literature
Project description:Bicuspid aortic valve (BAV) patients have an increased incidence of developing aortic dilation. Despite its importance, the pathogenesis of aortopathy in BAV is still largely undetermined. Nowadays, intense focus falls both on BAV morphology and progression of valvular dysfunction and on the development of aortic dilation. However, less is known about the relationship between aortic valve morphology and aortic dilation. A better understanding of the molecular pathways involved in the homeostasis of the aortic wall, including the extracellular matrix, the plasticity of the vascular smooth cells, TGFβ signaling, and epigenetic dysregulation, is key to enlighten the mechanisms underpinning BAV-aortopathy development and progression. To date, there are two main theories on this subject, i.e., the genetic and the hemodynamic theory, with an ongoing debate over the pathogenesis of BAV-aortopathy. Furthermore, the lack of early detection biomarkers leads to challenges in the management of patients affected by BAV-aortopathy. Here, we critically review the current knowledge on the driving mechanisms of BAV-aortopathy together with the current clinical management and lack of available biomarkers allowing for early detection and better treatment optimization.
| S-EPMC6023468 | biostudies-literature
Project description:ObjectiveTo explore the micromechanical, biochemical, and microstructural differences between bicuspid aortic valve aneurysm (BAV-A) and tricuspid aortic valve idiopathic degenerative aneurysm (DA), compared with normal aorta.MethodsAortic tissue was obtained from patients undergoing aneurysmal repair surgery (BAV-A; n = 15 and DA; n = 15). Control tissue was obtained from aortic punch biopsies during coronary artery bypass graft surgery (n = 9). Nanoindentation was used to determine the elastic modulus on the medial layer. Glycosaminoglycan, collagen, and elastin levels were measured using biochemical assays. Verhoeff Van Gieson-stained cross-sections were imaged for elastin microstructural quantification.ResultsThe elastic modulus was more than 20% greater for BAV-A relative to control and DA (signifying a loss of compliance). No significance difference between control and DA were observed. Collagen levels for BAV-A (36.9 ± 7.4 μg/mg) and DA (49.9 ± 10.9 μg/mg) were greater compared with the control (30.2 ± 13.1 μg/mg). Glycosaminoglycan and elastin levels were not significant between the groups. Elastin segments were uniform throughout the control. Aneurysmal tissues had less elastin segments close to the intima and adventitia layers. Both BAV-A and DA had elastin segments compacted in the media; however, elastin segments were highly fragmented in DA.ConclusionsBAV-A has a greater loss of aortic wall compliance relative to DA and the control. Although elastin levels were equal for all groups, spatial distribution of elastin provided a unique profile of matrix degradation for BAV-A. Elastin compaction within the media of BAV-A may have resulted from the altered hemodynamic pressure against the wall, which could explain for the stiffness of the tissue.
| S-EPMC7674632 | biostudies-literature
Project description:Bicuspid aortopathy occurs in approximately 50% of patients with bicuspid aortic valve (BAV), the most prevalent congenital cardiac malformation. Although different molecular players and etiological factors (genetic and hemodynamic) have been suggested to be involved in aortopathy predisposition and progression, clear etiophysiopathological mechanisms of disease are still missing. The isogenic (genetically uniform) hamster (T) strain shows 40% incidence of BAV, but aortic dilatations have not been detected in this model. We have performed comparative anatomical, histological and molecular analyses of the ascending aorta of animals with tricuspid aortic valve (TAV) and BAV from the T strain (TTAV and TBAV, respectively) and with TAV from a control strain (HTAV). Aortic diameter, smooth muscle apoptosis, elastic waviness, and Tgf-β and Fbn-2 expression were significantly increased in T strain animals, regardless of the valve morphology. Strain and aortic valve morphology did not affect Mmp-9 expression, whereas Mmp-2 transcripts were reduced in BAV animals. eNOS protein amount decreased in both TBAV and TTAV compared to HTAV animals. Thus, histomorphological and molecular alterations of the ascending aorta appear in a genetically uniform spontaneous hamster model irrespective of the aortic valve morphology. This is a direct experimental evidence supporting the genetic association between BAV and aortic dilatation. This model may represent a population of patients with predisposition to BAV aortopathy, in which increased expression of Tgf-β and Fbn-2 alters elastic lamellae structure and induces cell apoptosis mediated by eNOS. Patients either with TAV or BAV with the same genetic defect may show the same risk to develop bicuspid aortopathy.
| S-EPMC9393263 | biostudies-literature
Project description:OBJECTIVE:Aortic size-based criteria are of limited value in the prediction of aortic events, while most aortic events occur in patients with proximal aortic diameters < 50 mm. Serological biomarkers and especially circulating microRNAs (miRNAs) have been proposed as an elegant tool to improve risk stratification in patients with different aortopathies. Therefore, we aimed to evaluate the levels of circulating miRNAs in a surgical cohort of patients presenting with bicuspid aortic valve disease and distinct valvulo-aortic phenotypes. METHODS:We prospectively examined a consecutive cohort of 145 patients referred for aortic valve surgery: (1) Sixty three patients (mean age 47 ± 11 years, 92% male) with bicuspid aortic valve regurgitation and root dilatation (BAV-AR), (2) thirty two patients (mean age 59 ± 11 years, 73% male) with bicuspid aortic valve stenosis (BAV-AS), and (3) fifty patients (mean age 56 ± 14 years, 55% male) with tricuspid aortic valve stenosis and normal aortic root diameters (TAV-AS) who underwent aortic valve+/-proximal aortic surgery at a single institution. MicroRNAs analysis included 11 miRNAs, all published previously in association with aortopathies. Endpoints of our study were (1) correlation between circulating miRNAs and aortic diameter and (2) comparison of circulating miRNAs in distinct valvulo-aortic phenotypes. RESULTS:We found a significant inverse linear correlation between circulating miRNAs levels and proximal aortic diameter in the whole study cohort. The strongest correlation was found for miR-17 (r = -0.42, p < 0.001), miR-20a (r = -0.37, p < 0.001), and miR-106a (r = -0.32, p < 0.001). All miRNAs were significantly downregulated in BAV vs. TAV with normal aortic root dimensions Conclusions: Our data demonstrate a significant inverse correlation between circulating miRNAs levels and the maximal aortic diameter in BAV aortopathy. When comparing miRNAs expression patterns in BAV vs. TAV patients with normal aortic root dimensions, BAV patients showed significant downregulation of analyzed miRNAs as compared to their TAV counterparts. Further multicenter studies in larger cohorts are needed to further validate these results.
| S-EPMC7020030 | biostudies-literature
Project description:ObjectiveBicuspid aortic valve is a common risk factor for thoracic aortic aneurysm and dissection. Guidelines for elective ascending aortic intervention (AAI) in bicuspid aortic valve are derived from limited evidence, and the extent of practice variation due to patient and provider characteristics is unknown. Using data from 2 large cardiovascular registries, we investigated factors that influence decisions for AAI.MethodsAll bicuspid aortic valve cases with known aortic diameters and surgical status were included. We used multivariable logistic regression to profile predictors of isolated aortic valve replacement (AVR) or AVR+AAI, stratified by patient characteristics, surgical indications, and institution.ResultsWe studied 2861 subjects at 18 institutions from 1996 to 2015. The median aortic diameter of patients who underwent AVR+AAI varied widely across institutions (39-52 mm). Aortic diameters were <45 mm in 38% of patients undergoing AVR+AAI. Patients who underwent AAI at <45 mm, compared with those managed nonoperatively, were younger (54 ± 13 vs 61 ± 15 years; P < .001) with more frequent aortic stenosis (53% vs 28%; P < .001) and regurgitation (52% vs 18%; P < .001).ConclusionsClinical and institutional factors influence the timing of AAI and are associated with significant variability in ascending aortic diameter at AAI across institutions. More than one third of patients with a bicuspid aortic valve undergo AAI at aortic diameters <45 mm. Long-term outcomes of this subgroup of patients, who may manifest earlier and more severe disease, are needed to determine the risk-benefit ratio of routine aortic interventions at smaller diameters.
| S-EPMC7035185 | biostudies-literature
Project description:Introduction: Morphology of bicuspid aortic valve (BAV) may have implication in the associated pathologies including aortic stenosis (AS), aortic insufficiency (AI) and aortic dilation. The aim of this study is to investigate the frequency and patterns of valvular dysfunction and aortopathy associated with different phenotypes of BAV in a referral center in northwest of Iran. Methods: In this prospective study patients who presented to our echocardiography lab between January 2014 and December 2015 and were diagnosed with BAV were assessed. Frequency of various BAV phenotypes and their association with valvular dysfunction and aortopathy was evaluated. A P value less than 0.05 was considered statistically significant. Results: The average age of the study patients was 40±16 years, with predominance of male sex (72%). Patients with anteroposteriorly located BAV (BAV-AP) phenotype constituted majority of our cases with prevalence of 62.7%, while 37.3% of cases had right-left (BAV-RL) located valves. BAV-RL patients when compared to BAV-AP patients had higher frequencies of dilated aortic arch (25% vs. 4.3%, P < 0.001), AS (56.3% vs. 31.4%, P < 0.001), mass or vegetation on aortic valve (14.3 vs. 6.4%, P = 0.023) and lower frequencies of dilated aortic root (42.9% vs. 57.4%, P = 0.01), aortic insufficiency (68.8% vs. 79.8%, P = 0.034) and co-arctation of aorta (3.6% vs. 11.7%, P = 0.01). Conclusion: There seems to be a relationship between various BAV phenotypes, and frequency and pattern of aortic valve dysfunction and aortopathy. These findings suggest that examining leaflet morphology in BAV might help in risk stratification of these patients.
| S-EPMC6335981 | biostudies-other
Project description:MicroRNAs (miRNAs) may serve as elegant tool to improve risk stratification in bicuspid aortic valve (BAV)-associated aortopathy. However, the exact pathogenetic pathway by which miRNAs impact aortopathy progression is unknown. Herewith, we aimed to analyze the association between circulating miRNAs and rare variants of aortopathy-related genes. 63 BAV patients (mean age 47.3±11.3 years, 92% male) with a root dilatation phenotype, who underwent aortic valve+/-proximal aortic surgery at a single institution (mean post-AVR follow-up 10.3±6.9 years) were analyzed. A custom-made HaloPlex HS panel including 20 aortopathy-related genes was used for the genetic testing. miRNAs were extracted from whole blood and miRNA analysis was performed using miRNA-specific assay. Study endpoint was the association between circulating miRNAs and rare genetic variants in the aortopathy gene panel. The study cohort was divided into a subgroup with rare variants vs. a subgroup without rare variants based on the presence of rare variants in the respective genes (i.e., at least one variant present). The genetic analysis yielded n = 6 potentially and likely pathogenic rare variants within the NOTCH1 gene as being the most common finding. Univariate analysis between blood miRNAs and NOTCH1 variants revealed a significantly lower expression of miR-145 in the subgroup of patients with NOTCH1 variants vs. those without NOTCH1 variants (i.e., delta Ct 4.95±0.74 vs. delta Ct 5.57±0.78, p = 0.04). Our preliminary data demonstrate a significant association between blood miR-145 expression and the presence of rare NOTCH1 variants. This association may be indicative of a specific pathogenetic pathway in the development of genetically-triggered bicuspid aortopathy.
| S-EPMC6066209 | biostudies-literature
Project description:BackgroundSuspected genetic causes for extracellular matrix (ECM) dysregulation in the ascending aorta in patients with bicuspid aortic valves (BAV) have influenced strategies and thresholds for surgical resection of BAV aortopathy. Using 4-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we have documented increased regional wall shear stress (WSS) in the ascending aorta of BAV patients.ObjectivesThis study assessed the relationship between WSS and regional aortic tissue remodeling in BAV patients to determine the influence of regional WSS on the expression of ECM dysregulation.MethodsBAV patients (n = 20) undergoing ascending aortic resection underwent pre-operative 4D flow CMR to regionally map WSS. Paired aortic wall samples (i.e., within-patient samples obtained from regions of elevated and normal WSS) were collected and compared for medial elastin degeneration by histology and ECM regulation by protein expression.ResultsRegions of increased WSS showed greater medial elastin degradation compared to adjacent areas with normal WSS: decreased total elastin (p = 0.01) with thinner fibers (p = 0.00007) that were farther apart (p = 0.001). Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor β-1 (p = 0.04), matrix metalloproteinase (MMP)-1 (p = 0.03), MMP-2 (p = 0.06), MMP-3 (p = 0.02), and tissue inhibitor of metalloproteinase-1 (p = 0.04) in elevated WSS regions, indicating ECM dysregulation in regions of high WSS.ConclusionsRegions of increased WSS correspond with ECM dysregulation and elastic fiber degeneration in the ascending aorta of BAV patients, implicating valve-related hemodynamics as a contributing factor in the development of aortopathy. Further study to validate the use of 4D flow CMR as a noninvasive biomarker of disease progression and its ability to individualize resection strategies is warranted.
| S-EPMC4545965 | biostudies-literature
Project description:ImportanceThe prevalence and characteristics of bicuspid aortic valve (BAV) are mainly reported from selected cohorts. BAV is associated with aortopathy, but it is unclear if it represents a fetal developmental defect or is secondary to abnormal valve dynamics.ObjectiveTo determine the prevalence of BAV and BAV subtypes and to describe the associated aortopathy in a large, population-based cohort of newborns.Design, setting, and participantsThe Copenhagen Baby Heart Study was a cross-sectional, population-based study open to all newborns born in Copenhagen between April 1, 2016, and October 31, 2018. Newborns with BAV were matched 1:2 to newborns with a tricuspid aortic valve (non-BAV group) on sex, singleton/twin pregnancy, gestational age, weight, and age at time of examination.ExposuresTransthoracic echocardiography within 60 days after birth.Main outcomes and measuresPrimary outcome was BAV prevalence and types, ie, number of raphes and spatial orientation of raphes or cusps (no raphes), according to the classification system of Sievers and Schmidtke (classified as type 0, 1, or 2, with numbers indicating the number of raphes). Secondary outcome was valve function and BAV-associated aortopathy, defined as aortic diameter z score of 3 or greater or coarctation.ResultsIn total, 25 556 newborns (51.7% male; mean age, 12 [SD, 8] days) underwent echocardiography. BAV was diagnosed in 196 newborns (prevalence, 0.77% [95% CI, 0.67%-0.88%]), with male-female ratio 2.1:1. BAV was classified as type 0 in 17 newborns (8.7% [95% CI, 5.5%-13.5%]), type 1 in 178 (90.8% [95% CI, 86.0%-94.1%]) (147 [75.0% {95% CI, 68.5%-80.5%}] right-left coronary raphe, 27 [13.8% {95% CI, 9.6%-19.3%}] right coronary-noncoronary raphe, 4 [2.0% {95% CI, 0.8%-5.1%}] left coronary-noncoronary raphe), and type 2 in 1 (0.5% [95% CI, 0.1%-2.8%]). Aortic regurgitation was more prevalent in newborns with BAV (n = 29 [14.7%]) than in those without BAV (1.3%) (absolute % difference, 13.4% [95% CI, 7.8%-18.9%]; P < .001). Newborns with BAV had higher flow velocities across the valve (0.67 [95% CI, 0.65-0.69] m/s vs 0.61 [95% CI, 0.60-0.62] m/s; mean difference, 0.06 m/s [95% CI, 0-0.1]) and larger aortic root and tubular ascending aortic diameters than those without BAV (10.7 [95% CI, 10.7-10.9] mm vs 10.3 [95% CI, 10.2-10.4] mm; mean difference, 0.43 mm [95% CI, 0.2-0.6 mm] and 9.8 [95% CI, 9.6-10.0] mm vs 9.4 [95% CI, 9.3-9.5] mm; mean difference, 0.46 mm [95% CI, 0.30-0.70], respectively) (P < .001 for all). Aortopathy was seen in 65 newborns (33.2%) with BAV (62 with aortic z score ≥3; 3 with coarctation).Conclusions and relevanceAmong newborns in Copenhagen, the prevalence of BAV was 0.77%. Aortopathy was common in newborns with BAV, suggesting that it also represents a fetal malformation.
| S-EPMC7873775 | biostudies-literature