Altered Pattern of Gene Expression in Thoracic Aortic Aneurysms in Patients with Trileaflet and Bileaflet Aortic Valve: A Pilot Study Using Affymetrix Gene Chips

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

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The Value of Circulating Biomarkers in Bicuspid Aortic Valve-Associated Aortopathy

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0036-1583525 ◽

2016 ◽

Vol 66 (04) ◽

pp. 278-286 ◽

Cited By ~ 7

Author(s):

Shiho Naito ◽

Mathias Hillebrand ◽

Alexander Bernhardt ◽

Annika Jagodzinski ◽

Lenard Conradi ◽

...

Keyword(s):

Aortic Valve ◽

Risk Stratification ◽

Bicuspid Aortic Valve ◽

Aortic Aneurysms ◽

Conventional Imaging ◽

Circulating Biomarkers ◽

Screening Process ◽

Cross Sectional ◽

Thoracic Aortic Aneurysms ◽

Definition Of

AbstractTraditional risk stratification model of bicuspid aortic valve (BAV) aortopathy is based on measurement of maximal cross-sectional aortic diameter, definition of proximal aortic shape, and aortic stiffness/elasticity parameters. However, conventional imaging-based criteria are unable to provide reliable information regarding the risk stratification in BAV aortopathy, especially considering the heterogeneous nature of BAV disease. Given those limitations of conventional imaging, there is a growing clinical interest to use circulating biomarkers in the screening process for thoracic aortic aneurysms as well as in the risk-assessment algorithms. We aimed to systematically review currently available biomarkers, which may be of value to predict the natural evolution of aortopathy in individuals with BAV.

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Atlas-Based Evaluation of Hemodynamic in Ascending Thoracic Aortic Aneurysms

Applied Sciences ◽

10.3390/app12010394 ◽

2021 ◽

Vol 12 (1) ◽

pp. 394

Author(s):

Chiara Catalano ◽

Valentina Agnese ◽

Giovanni Gentile ◽

Giuseppe M. Raffa ◽

Michele Pilato ◽

...

Keyword(s):

Aortic Valve ◽

Fluid Shear Stress ◽

Aortic Aneurysms ◽

Disease Assessment ◽

Complex Nature ◽

Thoracic Aortic Aneurysms ◽

Statistical Shape ◽

Specific Shape ◽

Mode 3 ◽

Aortic Size

Atlas-based analyses of patients with cardiovascular diseases have recently been explored to understand the mechanistic link between shape and pathophysiology. The construction of probabilistic atlases is based on statistical shape modeling (SSM) to assess key anatomic features for a given patient population. Such an approach is relevant to study the complex nature of the ascending thoracic aortic aneurysm (ATAA) as characterized by different patterns of aortic shapes and valve phenotypes. This study was carried out to develop an SSM of the dilated aorta with both bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV), and then assess the computational hemodynamic of virtual models obtained by the deformation of the mean template for specific shape boundaries (i.e., ±1.5 standard deviation, σ). Simulations demonstrated remarkable changes in the velocity streamlines, blood pressure, and fluid shear stress with the principal shape modes such as the aortic size (Mode 1), vessel tortuosity (Mode 2), and aortic valve morphologies (Mode 3). The atlas-based disease assessment can represent a powerful tool to reveal important insights on ATAA-derived hemodynamic, especially for aneurysms which are considered to have borderline anatomies, and thus challenging decision-making. The utilization of SSMs for creating probabilistic patient cohorts can facilitate the understanding of the heterogenous nature of the dilated ascending aorta.

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Abstract 760: Alterations in Fibroblast Phenotype during Murine Thoracic Aortic Aneurysm Development

Circulation ◽

10.1161/circ.118.suppl_18.s_614 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Jeffrey A Jones ◽

Juozas A Zavadzkas ◽

Eileen I Chang ◽

Christine N Koval ◽

Robert E Stroud ◽

...

Keyword(s):

Gene Expression ◽

Fold Increase ◽

Vascular Wall ◽

Aortic Aneurysms ◽

Phenotypic Change ◽

Structural Protein ◽

Altered Expression ◽

Thoracic Aortic Aneurysms ◽

Elevated Expression ◽

Or Genes

Thoracic aortic aneurysms (TAAs) result from maladaptive remodeling of the vascular extracellular matrix (ECM). In addition to structural protein changes, resident cellular profiles are altered leaving the fibroblast as the predominant cell type within the vascular wall. The present study tests the hypothesis that fibroblast phenotype is also altered during TAA development. Primary murine aortic fibroblasts were isolated from normal (n=4) and TAA aortas (n=3; 4-wks post-induction; topical 0.5M CaCl 2 15 min) by the outgrowth method. Cultures were established and passages 3–5 were used for gene expression profiling in the absence of stimulation. Relative expression of 30 genes (MMPs, ECM proteins, transcription factors) normalized to 4 house keeping genes was measured by quantitative real-time PCR. Genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized Ct values (t-test, TAA vs. control; p<0.05) were considered to have altered expression Steady state gene expression of 4-wk TAA versus normal fibroblasts revealed elevated expression of Mmp2, Mmp11, Mmp15, Col1a1, Col1a2, Col3a1, Eln, Lamb2, Fn1, Fbn2, Spp1, Sparc, Fos, and Fosb, and decreased expression of Mmp3, Timp3, Ltbp1, Sp1, and Junb ( Figure ). This study demonstrates for the first time that isolated aortic fibroblasts from 4-wk TAAs possess a unique gene expression profile as compared to normal fibroblasts. This suggests they have undergone a stable phenotypic change, which may be the result of a clonal expansion of a subset of cells, and may play a significant role in TAA development through the enhancement of ECM proteolysis.

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Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms

International Heart Journal ◽

10.1536/ihj.46.265 ◽

2005 ◽

Vol 46 (2) ◽

pp. 265-277 ◽

Cited By ~ 32

Author(s):

Tsuyoshi Taketani ◽

Yasushi Imai ◽

Tetsuro Morota ◽

Koji Maemura ◽

Hiroyuki Morita ◽

...

Keyword(s):

Gene Expression ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms

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Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2007.02.041 ◽

2007 ◽

Vol 134 (2) ◽

pp. 290-296 ◽

Cited By ~ 171

Author(s):

Stephen H. McKellar ◽

David J. Tester ◽

Marineh Yagubyan ◽

Ramanath Majumdar ◽

Michael J. Ackerman ◽

...

Keyword(s):

Aortic Valve ◽

Bicuspid Aortic Valve ◽

Aortic Valve Disease ◽

Aortic Aneurysms ◽

Valve Disease ◽

Thoracic Aortic Aneurysms ◽

Notch1 Mutations

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Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00178.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. H103-H113 ◽

Cited By ~ 8

Author(s):

Jungsil Kim ◽

Jesse D. Procknow ◽

Hiromi Yanagisawa ◽

Jessica E. Wagenseil

Keyword(s):

Gene Expression ◽

Matrix Protein ◽

Mechanical Response ◽

Aortic Aneurysms ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Newborn Mice ◽

Thoracic Aortic Aneurysms ◽

Neutrophil Collagenase

Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 ( Fbln4−/−) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4−/− and Fbln4+/+ mice. Fbln4−/− AA has increased diameters compared with Fbln4+/+ AA and Fbln4−/− DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4−/− aortas. Fbln4−/− aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4−/− aortas compared with Fbln4+/+. Additional genes in both pathways, as well as matrix metalloprotease-8 ( Mmp8), are upregulated specifically in Fbln4−/− AA compared with Fbln4+/+ AA and Fbln4−/− DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4−/− AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.

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