The Genetics and Typical Traits of Thoracic Aortic Aneurysm and Dissection

Bento, Jotte Rodrigues; Meester, Josephina; Luyckx, Ilse; Peeters, Silke; Verstraeten, Aline; Loeys, Bart

doi:10.1146/annurev-genom-111521-104455

Cited by 30 publications

(33 citation statements)

References 146 publications

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“…14 These genes encode regulatory molecules for the extracellular matrix (FBN1, FBN2, COL1A1, COL1A2, and COL3A1), the cytoskeleton in smooth muscle cells (ACTA2, MYH11, and MYLK), and the TGF-β signaling pathway (TGFβ2, TGFBR1, TGFBR2, SMAD3, and SLC2A10). 14 It is now well recognized that certain genes can alter the natural course of aortic disease by making patients more vulnerable to AAEs (such as rupture and dissection) at small aortic sizes, 15,16 well below the traditional intervention criteria, 17,18 and at a significantly younger age. This was first recognized for patients with mutations in the FBN1 gene (Marfan's syndrome), for whom the intervention criteria were lowered in the the American and European Aortic Disease guidelines.…”

Section: Genesmentioning

confidence: 99%

Nonsize Criteria for Surgical Intervention on the Ascending Thoracic Aorta

Ziganshin

Zafar

2023

Aorta (Stamford)

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For decades, aortic surgery has relied on size criteria for intervention on the ascending aorta. While diameter has served well, diameter alone falls short of an ideal criterion. Herein, we examine the potential application of other, nondiameter criteria in aortic decision-making. These findings are summarized in this review. We have conducted multiple investigations of specific alternate nonsize criteria by leveraging our extensive database, which includes complete, verified anatomic, clinical, and mortality data on 2,501 patients with thoracic aortic aneurysm (TAA) and dissections (198 Type A, 201 Type B, and 2102 TAAs). We examined 14 potential intervention criteria. Each substudy had its own specific methodology, reported individually in the literature. The overall findings of these studies are presented here, with a special emphasis on how the findings can be incorporated into enhanced aortic decision-making—above and beyond sheer diameter. The following nondiameter criteria have been found useful in decision-making regarding surgical intervention. (1) Pain: In the absence of other specific cause, substernal chest pain mandates surgery. Well-developed afferent neural pathways carry warning signals to the brain. (2) Aortic length/tortuosity: Length is emerging as a mildly better predictor of impending events than diameter. (3) Genes: Specific genetic aberrations provide a powerful predictor of aortic behavior; malignant genetic variants obligate earlier surgery. (4) Family history: Aortic events closely follow those in relatives with a threefold increase in likelihood of aortic dissection for other family members once an index family dissection has occurred. (5) Bicuspid aortic valve: Previously thought to increase aortic risk (as a “Marfan light” situation), current data show that bicuspid valve is not a predictor of higher risk. (6) Diabetes actually protects against aortic events, via mural thickening and fibrosis. (7) Biomarkers: A specialized “RNA signature test” identifies aneurysm-bearing patients in the general population and promises to predict impending dissection. (8) Aortic stress: Blood pressure (BP) elevation from anxiety/exertion precipitates dissection, especially with high-intensity weightlifting. (9) Root dilatation imposes higher dissection risk than supracoronary ascending aneurysm. (10) Inflammation on positron emission tomography (PET) imaging implies high rupture risk and merits surgical intervention. (11) A KIF6 p.Trp719Arg variant elevates aortic dissection risk nearly two-fold. (12) Female sex confers some increased risk, which can be largely accommodated by using body-size-based nomograms (especially height nomograms). (13) Fluoroquinolones predispose to catastrophic dissection events and should be avoided rigorously in aneurysm patients. (14) Advancing age makes the aorta more vulnerable, increasing likelihood of dissection. In conclusion, nondiameter criteria can beneficially be brought to bear on the decision to observe or operate on specific TAA.

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Section: Genesmentioning

confidence: 99%

Nonsize Criteria for Surgical Intervention on the Ascending Thoracic Aorta

Ziganshin

Zafar

2023

Aorta (Stamford)

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“…Prophylactic surgery of TAA patients reduces the mortality rate to approximately 5%, but comes along with a relatively high risk of complications [ 6 ]. To date, mutations in over 40 genes have been described to cause TAA [ 7 ▪▪ ].…”

Section: Introductionmentioning

confidence: 99%

Structural genomic variants in thoracic aortic disease

Meester

Hebert

Loeys

2023

Current Opinion in Cardiology

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Purpose of review Structural genomic variants have emerged as a relevant cause for several disorders, including intellectual disability, neuropsychiatric disorders, cancer and congenital heart disease. In this review, we will discuss the current knowledge about the involvement of structural genomic variants and, in particular, copy number variants in the development of thoracic aortic and aortic valve disease. Recent findings There is a growing interest in the identification of structural variants in aortopathy. Copy number variants identified in thoracic aortic aneurysms and dissections, bicuspid aortic valve related aortopathy, Williams-Beuren syndrome and Turner syndrome are discussed in detail. Most recently, the first inversion disrupting FBN1 has been reported as a cause for Marfan syndrome. Summary During the past 15 years, the knowledge on the role of copy number variants as a cause for aortopathy has grown significantly, which is partially due to the development of novel technologies including next-generation sequencing. Although copy number variants are now often investigated on a routine basis in diagnostic laboratories, more complex structural variants such as inversions, which require the use of whole genome sequencing, are still relatively new to the field of thoracic aortic and aortic valve disease.

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“…Collectively, these genes and others highlight the major molecular pathways involved in aortic biology: ECM adhesion and mechanosensing, vascular smooth muscle cell (VSMC) contractile function, and TGF-β (transforming growth factor beta) signaling, the latter of which regulates VSMC phenotype modulation from a contractile to a synthetic, proliferative state. 6,7 While family-based studies have provided a starting point for causal gene discovery, much remains unknown about the genetic basis of aortic traits, particularly in individuals with sporadic or late-onset forms of thoracic aortopathy. A small number of case-control exome sequencing studies in this population have identified rare variants in a small proportion of individuals, 6,9 but the lack of relative success with this approach suggests that low-frequency, high-impact mutations account for the minority of population-scale variation in aortic disease.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

Raghavan,

Pirruccello,

Ellinor

et al. 2024

ATVB

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Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.

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The Genetics and Typical Traits of Thoracic Aortic Aneurysm and Dissection

Cited by 30 publications

References 146 publications

Nonsize Criteria for Surgical Intervention on the Ascending Thoracic Aorta

Nonsize Criteria for Surgical Intervention on the Ascending Thoracic Aorta

Structural genomic variants in thoracic aortic disease

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

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