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Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55 Page 3 of 15

[7]
this article. In contrast, ns-TAAD is isolated to the aorta with no associated syndromic defects .
Approximately 5% of patients presenting with TAAD have the disease due to syndromic aortopathies,
[8]
implying that 95% are due to ns-TAAD or are sporadic . Although much has yet to be investigated through
pedigree and gene sequencing analysis, current data suggests that up to 20% of TAADs not due to MFS,
LDS, or vEDS have a familial component, i.e., they are ns-TAAD . The myriad of potentially pathologic
[9]
genetic variants underlying ns-TAAD are only just beginning to be elucidated.

Postmortem studies
A true incidence of acute aortic dissection remains unknown as many of those affected do not survive to
receive intervention and treatment. Tanaka et al. conducted a retrospective study of 311 patients who
succumbed to out-of-hospital cardiopulmonary arrests and found 7% of those patients experienced acute
[1]
type A aortic dissections . A systematic review by Lovatt et al. analyzing 12 studies including 1,663 patients
estimated the overall rate of misdiagnosis of aortic dissection to be 33.8% . These findings suggest an
[10]
underestimation of the prevalence of fatal dissections, specifically in patients presenting with chest pain,
back pain, and syncope attributed to acute coronary syndrome, stroke, or pulmonary embolism and/or the
absence of "typical features" of acute aortic dissection such as widened mediastinum on chest X-ray. A more
recent multi-institutional autopsy study of acute dissection fatalities in 35 patients, all under the age of 35
years, aimed to stratify risk factors for dissection. Forty-three percent were associated with bicuspid aortic
valve (BAV), followed by 31% with no valvulopathy or syndromic diagnosis association. Notably, 16 (47%)
patients experiencing prodromal symptoms (e.g., chest pain, malaise, nausea, back pain) were misdiagnosed
by a physician as having anxiety, gastroenteritis, esophageal reflux or spasm, pneumonia, or pleuritic
pain .
[11]

Milewicz et al. reviewed autopsy reports in conjunction with medical records in six families with multiple
members affected with TAAD. They found that the inheritance patterns were consistent with an autosomal
dominant pattern but also displayed variable penetrance, resulting in difficulty in accurately identifying at-
risk individuals. In addition, two of these families did not have an identifiable known gene mutation .
[12]

Pedigree analyses
A familial pattern in ns-TAAD was first identified in 1997 using a pedigree analysis of first-degree relatives
of 158 affected probands. The study demonstrated a familial aggregation pattern but no clear Mendelian
pattern of inheritance. Additionally, first-degree relatives (FDRs) of probands with thoracic aortic dissection
were found to have a three-fold higher risk of sudden death . Several familial studies have documented the
[13]
heterogeneous nature of the inheritance pattern associated with ns-TAAD. Coady et al. performed a
pedigree analysis from 135 probands and found variable patterns of inheritance with 38% as autosomal
dominant, 27% as autosomal recessive, and 23% as X-linked dominant or autosomal dominant, supporting
the idea of genetic heterogeneity in familial ns-TAAD . These findings are corroborated by other groups.
[14]
Albornoz et al. investigated pedigrees of 520 patients presenting with TAAD . Twenty-one percent
[9]
exhibited a familial pattern, with 77% following an autosomal dominant inheritance pattern with variable
phenotypic expression. Studies over the past two decades by Milewicz et al. have also revealed that up to
20% of ns-TAAD is typically autosomal dominant, with decreased penetrance indicating the presence of
heterozygous pathogenic variants [13,15] .

There is accumulating evidence that familial risk for acute aortic pathology confers an increased mortality
risk for relatives of patients with thoracic aortic disease. A recent pedigree analysis of 100 probands found
that the annual probability of developing an acute dissection was 2.77 times higher in FDRs of affected
individuals compared to those without a family history of aortic dissection. They also found time to