scholarly journals The genetics and biomechanics of thoracic aortic diseases

2019 ◽  
Vol 1 (1) ◽  
pp. R13-R25
Author(s):  
Amer Harky ◽  
Ka Siu Fan ◽  
Ka Hay Fan
Keyword(s):  
Structural Instability ◽  
Aortic Aneurysms ◽  
Telomere Dysfunction ◽  
Aortic Diseases ◽  
Thoracic Aortic Aneurysms ◽  
Treatment And Prevention ◽  
Inflammatory State ◽  
Biomechanical Changes ◽  
Thoracic Aneurysms ◽  
Aortic Dissections

Thoracic aortic aneurysms and aortic dissections (TAAD) are highly fatal emergencies within cardiothoracic surgery. With increasing age, thoracic aneurysms become more prevalent and pose an even greater threat when they develop into aortic dissections. Both diseases are multifactorial and are influenced by a multitude of physiological and biomechanical processes. Structural stability of aorta can be disrupted by genes, such as those for extracellular matrix and contractile protein, as well as telomere dysfunction, which leads to senescence of smooth muscle and endothelial cells. Biomechanical changes such as increased luminal pressure imposed by hypertension are also very prevalent and lead to structural instability. Furthermore, ageing is associated with a pro-inflammatory state that exacerbates degeneration of vessel wall, facilitating the development of both aortic aneurysms and aortic dissection. This literature review provides an overview of the aetiology and pathophysiology of both thoracic aneurysms and aortic dissections. With an improved understanding, new therapeutic targets may eventually be identified to facilitate treatment and prevention of these diseases.

Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Siddharth K Prakash ◽  
Angela T Yetman ◽  
Hector I Michelena ◽  
Malenka M Bissell ◽  
Yuli Y Kim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Early Onset ◽  
Rare Variants ◽  
De Novo ◽  
Late Onset ◽  
Copy Number Variants ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections

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.

scholarly journals A Case of Glucocorticoid Remediable Aldosteronism and Thoracoabdominal Aneurysms

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Anahita Shahrrava ◽  
Sunnan Moinuddin ◽  
Prajwal Boddu ◽  
Rohan Shah
Keyword(s):  
Salt Intake ◽  
Case Fatality ◽  
Aortic Aneurysms ◽  
High Rate ◽  
Thoracic Aortic Aneurysms ◽  
Familial Form ◽  
Early Use ◽  
Mineralocorticoid Antagonists ◽  
Aortic Dissections ◽  
Intracranial Vasculature

Glucocorticoid remediable aldosteronism (GRA) is rare familial form of primary aldosteronism characterized by a normalization of hypertension with the administration of glucocorticoids. We present a case of GRA and thoracoabdominal aneurysm complicated by multiple aortic dissections requiring complex surgical and endovascular repairs. Registry studies have shown a high rate of intracranial aneurysms in GRA patients with high case fatality rates. The association of thoracoabdominal aneurysms with GRA has not been described, thus far, in literature. Studies have shown that high tissue aldosterone levels concomitant with salt intake have a significant role in the pathogenesis of aneurysms and this may explain the formation of aneurysms in the intracranial vasculature and aorta. The association of GRA with thoracic aortic aneurysms needs to be further studied to develop screening recommendations for early identification and optimal treatment. Also, the early use of mineralocorticoid antagonists may have a significant preventive and attenuating effect in aneurysm formation, an association which needs to be confirmed in future studies.

Left Subclavian Artery Management in Endovascular Repair of Thoracic Aortic Aneurysms and Aortic Dissections

2003 ◽  
Vol 18 (5) ◽  
pp. 429-435 ◽  
Author(s):  
Kurt Tiesenhausen ◽  
Klaus A. Hausegger ◽  
Peter Oberwalder ◽  
Elisabeth Mahla ◽  
Maurice Tomka ◽  
...  
Keyword(s):  
Subclavian Artery ◽  
Endovascular Repair ◽  
Left Subclavian Artery ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections

scholarly journals Case Report: Occurrence of Severe Thoracic Aortic Aneurysms (Involving the Ascending, Arch, and Descending Segments) as a Result of Fibulin-4 Deficiency: A Rare Pathology With Successful Management

2021 ◽  
Vol 8 ◽  
Author(s):  
Paul Thomas ◽  
Aparna Venugopalan ◽  
Siddharth Narayanan ◽  
Thomas Mathew ◽  
Lakshmi Parvathi Deepti Cherukuwada ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Genetic Disorder ◽  
Female Child ◽  
Aortic Aneurysms ◽  
Cutis Laxa ◽  
Extracellular Matrix Protein ◽  
Successful Outcome ◽  
High Morbidity ◽  
Aortic Diseases ◽  
Thoracic Aortic Aneurysms

Aortic diseases requiring surgery in childhood are distinctive and rare. Very few reports in the literature account for the occurrence of multiple thoracic aortic aneurysms in the same pediatric patient because of a genetic cause. We report a rare occurrence of severe thoracic aortic aneurysms (involving the ascending, arch and descending aortic segments) with severe aortic insufficiency in a 7-year-old female child secondary to the extremely rare and often lethal genetic disorder, cutis laxa. She was eventually identified as a carrier of a homozygous EFEMP2 (alias FBLN4) mutation. This gene encodes the extracellular matrix protein fibulin-4, and its mutation is associated with autosomal recessive cutis laxa type 1B that leads to severe aortopathy with aneurysm formation and vascular tortuosity. Parents of the child were not known to be consanguineous. Significant symptomatic improvement in the patient could be discerned after timely intervention with the valve-sparing aortic root replacement (David V procedure) and a concomitant aortic arch replacement. This is a unique report with a successful outcome that highlights the occurrence of a rare hereditary aortopathy associated with a high morbidity and mortality, and the importance of an early diagnosis and timely management. It also offers insight to physicians in having a very broad differential and multimodal approach in handling rare pediatric cardio-pathologies with a genetic predisposition.

scholarly journals Regulation of SMC traction forces in human aortic thoracic aneurysms

2021 ◽  
Author(s):  
Claudie Petit ◽  
Ali-Akbar Karkhaneh Yousefi ◽  
Olfa Ben Moussa ◽  
Jean-Baptiste Michel ◽  
Alain Guignandon ◽  
...  
Keyword(s):  
Traction Force ◽  
Aortic Aneurysms ◽  
Force Generation ◽  
Dynamic Force ◽  
Generation Process ◽  
Traction Forces ◽  
Thoracic Aortic Aneurysms ◽  
And Gender ◽  
Thoracic Aneurysms ◽  
Future Work

AbstractSmooth muscle cells (SMCs) usually express a contractile phenotype in the healthy aorta. However, aortic SMCs have the ability to undergo profound changes in phenotype in response to changes in their extracellular environment, as occurs in ascending thoracic aortic aneurysms (ATAA). Accordingly, there is a pressing need to quantify the mechanobiological effects of these changes at single cell level. To address this need, we applied Traction Force Microscopy (TFM) on 759 cells coming from three primary healthy (AoPrim) human SMC lineages and three primary aneurysmal (AnevPrim) human SMC lineages, from age and gender matched donors. We measured the basal traction forces applied by each of these cells onto compliant hydrogels of different stiffness (4, 8, 12, 25 kPa). Although the range of force generation by SMCs suggested some heterogeneity, we observed that: 1. the traction forces were significantly larger on substrates of larger stiffness; 2. traction forces in AnevPrim were significantly higher than in AoPrim cells. We modelled computationally the dynamic force generation process in SMCs using the motor-clutch model and found that it accounts well for the stiffness-dependent traction forces. The existence of larger traction forces in the AnevPrim SMCs were related to the larger size of cells in these lineages. We conclude that phenotype changes occurring in ATAA, which were previously known to reduce the expression of elongated and contractile SMCs (rendering SMCs less responsive to vasoactive agents), tend also to induce stronger SMCs. Future work aims at understanding the causes of this alteration process in aortic aneurysms.

scholarly journals Recurrent Gain-of-Function Mutation in PRKG1 Causes Thoracic Aortic Aneurysms and Acute Aortic Dissections

2013 ◽  
Vol 93 (2) ◽  
pp. 398-404 ◽  
Author(s):  
Dong-chuan Guo ◽  
Ellen Regalado ◽  
Darren E. Casteel ◽  
Regie L. Santos-Cortez ◽  
Limin Gong ◽  
...  
Keyword(s):  
Aortic Aneurysms ◽  
Gain Of Function ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections
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