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Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55 Page 5 of 15

Most recently, a retrospective/prospective study utilizing the GenTAC (Genetically Triggered Thoracic
Aortic Aneurysm and Cardiovascular Conditions) Registry compared age and probability of elective surgery
for thoracic aortic aneurysm, any dissection, and cardiovascular mortalities in patients with BAV
[23]
aortopathy, MFS, LDS, vEDS, Turner syndrome, and ns-TAAD . BAV had the highest ratio of elective
ascending aortic replacement to emergent dissection surgery and the lowest risk of cardiovascular mortality.
Interestingly, in this study, ns-TAAD patients experienced an aortic surgery (elective or emergent) at a
more heterogenous age distribution and experienced dissection at a shorter time interval from diagnosis of
their aortopathy compared to s-TAAD patients. This highlights the need for a better understanding of ns-
TAAD to guide clinical management - diagnosis and timing of elective prophylactic repair.

Guidelines for MFS and BAV intervention and screening are notably better established, and a handful of
studies have compared outcomes of ns-TAAD to those with MFS and BAV. A single-institution prospective
surveillance study that sought to identify clinical and survival outcomes of patients with ns-TAAD in
comparison to patients with MFS or BAV identified 311 patients out of 760 with a diagnosis of ns-
TAAD . Dissection at presentation and a family history of dissection were more common in ns-TAAD
[24]
compared to BAV and MFS. Additionally, most fatal presentations due to aortopathy were in those with ns-
TAAD (79.5%) compared to MFS (16.4%) and BAV (4.1%). Interestingly, they found that the natural history
of ns-TAAD was comparable to the clinical course of an undiagnosed and untreated MFS. This posits the
hypothesis that the late diagnosis of TAAD at the time of dissection in ns-TAAD patients is due to a lack of
key extra-thoracic phenotypes that may trigger screening.

Sherrah et al. also found that a positive family history of dissection, younger age at diagnosis, and diagnosis
of ns-TAAD or MFS were independent predictors of mortality . As such, they advocate for management
[24]
guidelines of ns-TAAD that are similar to guidelines for MFS. Kimura et al. support a similar management
style. They conducted a multi-institutional retrospective review to determine outcomes of non-MFS acute
aortic dissection and found similar rates in ns-TAAD and MFS aortic growth rates (0.23 cm/year vs.
0.19 cm/year, respectively), concluding that ns-TAAD patients be managed with guidelines comparable to
[25]
those with MFS . Their conclusions are in line with guidelines proposed by other groups, which support a
more liberal threshold for elective repair of thoracic aortic aneurysm for ns-TAAD that mimics the lower
aortic diameter thresholds for s-TAAD.

Bicuspid aortopathy
As the most common congenital cardiac anomaly, BAV affects up to 2% of the general population and is
[26]
commonly associated with thoracic aortopathy . BAV is often an isolated condition and demonstrates
variability in phenotypic expression in association with aortic valve dysfunction (stenosis and/or
insufficiency) and TAAD. Familial clustering has been identified, but a specific genetic correlation has yet to
be elucidated . In addition to genetic variants, variability in presentation can be attributed to
[27]
hemodynamic factors from bicuspid valve morphology . However, the type of bicuspid morphology has
[28]
not been correlated with a specific aortic aneurysm phenotype [29,30] . While BAV can be associated with
syndromes (e.g., Turner syndrome), the majority of BAV cases are familial or sporadic. More than 80% of
individuals with BAV have no attributable family history. Furthermore, patients who have an asymptomatic
or minimally symptomatic BAV often go undiagnosed until presenting with dissection like those with ns-
[31]
TAAD . Several gene variants have been implicated in the development of both BAV and ns-TAAD:
ACTA2, TGFBR2, NOTCH-1, MUC4, and ROBO4 [32-34] . This supports the hypothesis that BAV disease is
polygenic with epigenetic modification, as a myriad of environmental and hemodynamic factors influence
the phenotypic expression of BAV morphology and the development of TAAD. Notable genetic mutations
identified in both BAV and ns-TAAD are implicated in abnormal TGF- signaling and dysregulation of
vascular smooth muscle cells (VSMC) predisposing to aneurysmal dilation [32,35] .