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Pisano et al. Vessel Plus 2020;4:33 I http://dx.doi.org/10.20517/2574-1209.2020.21 Page 3 of 13
[24]
established size criteria for surgery but may still be at significant risk of TAD. Accordingly, Davies et al.
showed in 2006 that indexing absolute aortic diameter to anthropometric measurements provides
individualized risk classification in patients with TAA. These authors introduced the concept of aortic size
index (ASI), defined as aortic size/body surface area, as a predictor of aortic dissection, rupture, and death.
2
In particular, they termed low risk patients as those with an ASI ≤ 2.05 cm/m . Moreover, weight fluctuates
throughout the lifespan and can be deliberately influenced. Unlike weight, height does not change during
adult life. Therefore, height-based relative aortic measures may be a more reliable long-term predictor of
[25]
risk. For this reason, Zafar et al. in 2018 introduced the concept of aortic height index (AHI), defined as
aortic size/height; and they assessed that AHI is as good as the ASI for risk stratification. They defined low
[26]
risk patients those with an AHI ≤ 2.43 cm/m. In addition, Acharya et al. introduced the concept of aortic
2
area/height ratio (IAAs) that was calculated indexing the aortic area (π x aortic radius ) to the patient height
and correlating it with the absolute aortic diameter. According these authors, a IAAs > 10 cm /m could be
2
considered the limit for early and proactive surgery to prevent TAD.
New evidences behind the diameter
Beside the aortic diameter, there is need to analyze other aspect of TAA that could better identify patients
in which aortic complications might occur at smaller aortic sizes than guidelines predict. In our opinion,
there are specific biological, morphological, and biomechanical markers of early rupture and dissection that
must be investigated in order to prevent deadly complication. In particular, in this review we focused our
attention on: (1) specific gene mutations that confer an increased risk for adverse outcomes, even at small
or normal aortic size; (2) histomorphological change and the quality of the aortic wall at the time of the
operation; (3) morphological markers of rupture and dissection in aortic root and ascending aorta; and (4)
flow abnormalities and the aortic wall shear stress.

Genetic features of thoracic aorta aneurysms
Recent progress in the understanding the pathophysiology of TAA have produced evidence suggesting
different molecular pathways and their genetic variants as potentiaL biomarkers of TAD, which might
be applied into TAA clinical management in order to prevent deadly complications [27-29] . These specific
gene mutations are reported to induce an increased risk for adverse outcomes, even at small or normal
aortic size [30,31] . The most interesting aspect is that this genetic risk is characteristic not only of syndromic
patients but also of non-syndromic patients [Figure 1]. The three main genetic syndrome associated with
[32]
[33]
TAA are: Marfan syndrome (mutations in the fibrillin-1 gene) [Figure 2]; Ehlers-Danlos syndrome
[34]
(mutations in COL3A1), and Loeys-Dietz syndrome (mutations in TGFβR1 or TGFβR2) . It has been
recognized that aortic dissection in Marfan syndrome patients can occur also at smaller sizes, therefore
we recommend early intervention. The non-syndromic TAA are divided into sporadic TAA and familial
TAA. In familial TAA, one or more family members are affected by TAA. Sporadic TAA is characterized
by sudden onset and no family history of aneurysm. On the other hands, many genes have been associated
[35]
to familial TAA [Figure 3]. Interestingly, recent evidences showed that the immune system and
inflammatory related genes have an important role in the onset and progression of sporadic TAAs even
at small aortic sizes. Among these inflammatory mediators, the Toll-like receptor 4 (TLR-4) is one of the
most important player [36-38] . The activation of TLR-4-mediated signaling pathway, both on endothelial cells
(ED) and vascular smooth muscle cells (VSMCs) [39,40] , could determine the deregulation of angiotensin
[44]
converting enzyme (ACE) [41-43] , nitric oxide (NO) , metalloproteinases (MMP) [45-48] associated with
endothelium dysfunction, extracellular matrix remodeling, and chronic inflammation causing medial
[49]
degeneration in sporadic TAA [Figure 4]. Evans et al. discovered that the interaction between TLR-4
and NO is one of the most important mechanisms by which aorta-derived mesenchymal progenitor cells
activate the immune and inflammatory cells. The increasing inflammation induces sporadic TAA onset
and progression. Li et al. reported the importance of TLR-4-mediated signaling pathway in regulating
[50]
the metalloproteinases-9 (MMP-9) expression in human aortic smooth muscle cells. Increased MMP-2 and