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Page 10 of 15 Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55

SMAD4 ubiquitination and proteasome-mediated protein degradation that correlated to reduced contractile
protein gene expression in VSMCs. Taken together, the data suggests a role for Smad4 mutation in
predisposing for early expression of ns-TAAD in a mechanism likely mediated through VSMCs.

Gene mutations in cell development
NOTCH1: Notch1 is a Type 1 transmembrane protein in the Notch signaling pathway that regulates
interactions between physically adjacent cells and is integral in cell development, including cardiogenesis,
valvulogenesis, and angiogenesis. Loss-of-function mutations in NOTCH1 have been identified in pedigree
and exon analyses in both familial and sporadic BAV patients [68,69] . McKellar et al. identified two novel
missense mutations (A1243V and P1390T) in NOTCH1 in 10.4% of patients with a BAV and thoracic aortic
aneurysm that were not present in patients with a BAV and normal aorta or patients with a trileaflet aortic
[70]
valve and thoracic aortic aneurysm . This investigation highlights a role for NOTCH mutations in the
pathogenesis of BAV aortopathy, but it was underpowered for statistical significance. Further research on
whether these variants are gain-of-function vs. loss-of-function mutations has yet to be published.

SCREENING AND MANAGEMENT GUIDELINES
The current guidelines for screening and management of known thoracic aortopathy primarily focus on
syndromic TAAD. The most recent consensus guidelines in the U.S., published in the Journal of the
American College of Cardiology in 2022, are a result of wide collaboration between medical, surgical, and
radiological experts . Additional comprehensive guidelines have been published by the Canadian
[6]
[72]
[71]
Cardiovascular Society and the European Society of Cardiology . These groups share similar
recommendations in most areas, including advocating for surgical intervention with an aneurysm diameter
between 4.5 and 5.0 cm and recommending screening in FDRs. Of note, the 2022 AHA/ACC guidelines
recommend the timing of surgical intervention for ns-TAAD to be a shared decision between patient and
surgeon (Class I) but also recommend prophylactic thoracic aortic repair when aortic diameter is greater
than or equal to 5.0 cm in asymptomatic, low-risk individuals or greater than or equal to 4.5 cm in high-risk
individuals. The differences between the American, Canadian, and European guidelines mostly pertain to
details related to screening modality and frequency as well as specifics in genetic testing.

The 2022 AHA/ACC guidelines include a section on genetic aortopathies with recommendations for genetic
testing and screening of family members for TAAD. Obtaining a multigenerational family history for
TAAD, unexplained death, and aneurysms in patients with aortic root/ascending aortic aneurysms, or
aortic dissection, as well as obtaining genetic testing to identify pathogenic variants are Class I
[6]
recommendations . At the time of writing of the 2022 guidelines, the HTAD genetic testing panels include
11 high-penetrance genes confirmed to be high risk for TAAD: TBN1, LOX, COL3A1, TGFBR1, TGFBR2,
SMAD3, TGFB2, ACTA2, MYH11, MYLK, and PRKG1 . The authors recognize the plethora of yet
[38]
unknown variants that predispose to TAAD and argue that families with a high incidence of TAAD
undergo genetic screening to advance our understanding of ns-TAAD. These guidelines also recommend
cascade screening - imaging family members with known/likely pathogenic variants to identify at-risk
individuals with enlarging asymptomatic thoracic aortas. Repeat screening in negative individuals is
recommended every five or ten years, depending on patient age.

An expert consensus from a large multidisciplinary team in The Netherlands similarly reviewed current
recommendations and literature with the purpose of providing more detailed criteria for identifying high-
risk individuals and a preferred screening modality and schedule . They recommend genetic testing
[73]
include the “core genes” implicated in ns-TAAD: ACTA2, FBN1, MATA2A, MFAP5, MYH11, MYLK,
PRKG1, SMAD3, and TGFBR2. Familial screening should begin at 25 years of age or 10 years before the