Bio-chemo-mechanics of the thoracic aorta

in Vascular Biology
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  • 1 Department of Respiratory Medicine, University Hospitals Birmingham, Birmingham, UK
  • 2 School of Medicine, Imperial College London, London, UK
  • 3 Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Liverpool, UK

Correspondence should be addressed to A Harky: amer.harky@lhch.nhs.uk

*(S Iddawela and A Ravendran contributed equally to this work)

The pathophysiology of thoracic aortic aneurysm and dissection is poorly understood, despite high mortality. An evidence review was conducted to examine the biomechanical, chemical and genetic factors involved in thoracic aortic pathology. The composition of connective tissue and smooth muscle cells can mediate important mechanical properties that allow the thoracic aorta to withstand and transmit pressures. Genetic syndromes can affect connective tissue and signalling proteins that interrupt smooth muscle function, leading to tissue failure. There are complex interplaying factors that maintain thoracic aortic function in health and are disrupted in disease, signifying an area for extensive research.

Abstract

The pathophysiology of thoracic aortic aneurysm and dissection is poorly understood, despite high mortality. An evidence review was conducted to examine the biomechanical, chemical and genetic factors involved in thoracic aortic pathology. The composition of connective tissue and smooth muscle cells can mediate important mechanical properties that allow the thoracic aorta to withstand and transmit pressures. Genetic syndromes can affect connective tissue and signalling proteins that interrupt smooth muscle function, leading to tissue failure. There are complex interplaying factors that maintain thoracic aortic function in health and are disrupted in disease, signifying an area for extensive research.

Introduction

Thoracic aortic aneurysms and dissections (TAAD) are relatively less common when compared with other cardiovascular diseases, but can result in significant mortality and morbidity if managed inappropriately (1). Mortality of untreated dissections can approach 50% if no intervention is initiated within 48 hours (2). Aneurysms can be classified according to type (saccularor fusiform) and location (thoracic, thoracoabdominal or abdominal). They can lead to rupture or dissection - however, it is important to note that the majority of dissections do not have a pre-existing aneurysm (3). There is a wide spectrum of thoracic aortic aneurysmal disease, r summarised in Table 1.

Table 1

Spectrum of thoracic aortic aneurysmal disease.

Forms of TAACharacteristicsExamples
DegenerativeMost common form of TAA
Weakening of connective tissue and tunica media
Includes cystic medial necrosis and elastin degradation
Genetic syndromeDefects in elastin and collagen lead to maladaptive responses to increased wall stressMarfan’s syndrome, vascular Ehler’s Danlos syndrome, Loey–Dietz syndrome, multisystemic smooth muscle dysfunction syndrome, Turner syndrome
NonsyndromicSingle gene mutations that lead to defective production and function of vascular endothelial cells or smooth muscle cellsFBN1, FOXE3
Associations with bicuspid aortic valve diseaseLeads to turbulent flow across it
Leads to dilation of the aortic root and subsequent aneurysm formation

Thoracic aortic aneurysms (TAA) may show significant variation in rate of growth and flow dynamics. There are several hypotheses suggested for this difference, ranging from embryonic origin to modelling of collagen (4). The risk factors that govern development of aneurysms and dissections are multifactorial, including hypertension and several genetic conditions. The pathophysiology of TAAD is poorly understood and attributed to several influences, involving a complex interplay between mechanical forces exerted by biological structure in the healthy and diseased thoracic aorta.

This literature review will explore evidence surrounding the genetic, biological and mechanical aspects of the thoracic aorta in health and disease to provide an understanding of how these factors may influence the development of TAAD. Deeper understanding of this area could guide more comprehensive models of risk stratification, enhance programmes for early detection and inform clinical decision-making.

Biology of the thoracic aorta

The thoracic aorta is a composite tube encompassing three distinct layers: the intima, media, and adventitia, as illustrated in Fig. 1 (5). The intima lines the lumen of the aorta and is comprised of a single layer of endothelial cells that is anchored to the underlying basement membrane (6). Endothelial cells are responsible for producing signals to control vessel tone and produce enzymes that are important for immune function, blood clotting and platelet adhesion (7). The basement membrane of the tunica intima is a highly specialised extra cellular matrix network consisting primarily of collagen type IV, laminin, perlecan and heparan sulphate proteoglycan (8).

Figure 1
Figure 1

Layers of the thoracic aorta.

Citation: Vascular Biology 3, 1; 10.1530/VB-20-0015

The tunica media mainly consists of elastin lamellae and smooth muscle cells and its role is to provide elasticity to the thoracic aorta (9). Elastin lamellae are networks of cross-linked elastin fibres which provide elastic energy storage for the vessel (10). Elastin fibres mainly consist of elastin and have various other microfibrillar proteins incorporated into the fibre (10). A notable microfibrillar protein is fibrillin, which interacts with other proteins to aid assembly, function, and long-term stability of the elastic fibres (10). Smooth muscle cells induce vasodilation and constriction. Heterogenous origins of smooth muscle cells have recently been reported in the thoracic aorta and provide a better insight into the variable susceptibilities to disease in different parts of the aorta. Sawada et al. demonstrated the different origin of smooth muscles cells between the ascending and descending thoracic aorta using genetically modified mice(11). Furthermore, the inner medial smooth muscle cells of the ascending aorta are derived from the second heart field while the outer medial cells are derived from cardiac neural crest (11). Conversely, the smooth muscle cells of the descending aorta are derived from single origin of somites, which are formed from the paraxial mesoderm (11). This could help explain the increased susceptibility to aneurysm in the ascending aorta compared to the descending aorta (12). However, actual functional differences due to the different origin warrant further research. The thickness of the tunica media is greatest in the thoracic aorta and decreases along the vessel. This is because elastin is greatest in the thoracic aorta and decreases further along distally from the heart, as a greater elastic energy storage is required to counter the stronger pulse closer to the heart (13). Therefore, the thoracic aorta is more susceptible to defects in extracellular matrix synthesis compared to distal regions of the aorta. The wall thickness-to-lumen diameter ratio remains constant as the lumen also decreases in diameter along the aorta (6).

The adventitia mainly comprises of fibroblasts, fibrocytes and bundles of collagen, which are supported by an external elastic lamina and together provide tensile strength. The vasa vasorum is woven into the adventitia and supplies oxygen and nutrients to the outer regions of the thoracic aorta. Recent evidence has suggested that the vasa vasorum of the thoracic aorta penetrates much deeper into the vessel wall compared to the distal aorta. Tonar et al. demonstrated the vasa vasorum density is higher in the tunica media and penetrates deeper towards the lumen in the thoracic aorta as compared to the abdominal aorta in porcine tissue (14). Furthermore, Federspiel et al. used immunohistochemical staining and confirmed these findings in human thoracic aorta (15). Collagen primarily provides tensile strength and in the adventitia collagen types I and III predominate (16). Collagen is arranged in a circumferential alignment, so that the unstressed tissues of collagen fibres are embedded in a wavy form in the soft ground matrix (16). Tensile strength makes the adventitia less stiff than the media, preventing overstretching and rupture (16).

All three layers create a dynamic vessel capable of withstanding large hemodynamic forces, which are most prominent in the thoracic aorta. Emerging evidence has suggested that the cells of the thoracic aorta are plastic and able to transform into other types of cells. Sandison et al. used prolonged time-lapse imaging to illustrate that vascular smooth muscle cells (VSMC) transitioned into non-contractile migratory macrophage-like cells (17). This could aid the understanding of certain pathology in the thoracic aorta which will be discussed later in the review.

Chemical pathways underlying thoracic aortic physiology

The smooth muscle cell contractile unit is composed of actin-containing thin filament and myosin thick filaments, along with regulatory proteins such as tropomyosin. The actin of the thin filament is a smooth muscle specific isoform which is encoded by the ACTA2 gene (18). The thick filament consists of a hexametric molecule composed of two myosin heavy chains, two essential light chains and two regulatory light chains. Smooth muscle cells contract mainly due to an increase in intracellular Ca2+ which is induced by neural, hormonal, and local factors (18). Intracellular Ca2+ binds to the protein Calmodulin forming a complex, which in turn binds to myosin light chain kinase to activate it (18). Active myosin light chain kinase phosphorylates the regulatory light chain of the myosin complex, which activates the actin-dependent ATPase activity of the myosin globular motor head and results in contraction (18). VSMC is mainly initiated by a decrease in intracellular Ca2+, which dissociates the Ca2+/Calmodulin complexes. However, this does not result in complete relaxation and instead maintains basal tone. This is an energy efficient state as cross-bridges are maintained (19).

Transforming growth factor-β (TGFB) is an important cytokine that has a vital role in the development and maintenance of the vascular extracellular matrix. TGFB is generally secreted in its inactive form where it is anchored with fibrillin-1 to form a large latent complex. Microfibrils (mainly fibrillin-1) regulate the bioavailability and local activity of TGFB. Activated TGFB stimulates the phosphorylation of receptor-regulated Smad protein, which regulates transcription of genes responsible for extracellular matrix synthesis and stabilisation. TGFB signalling has also been associated with extracellular matrix degradation through the upregulation of metalloproteinase-2 and metalloproteinase-9. Recent evidence has shown that TGFB appears to have a greater role in extracellular matrix synthesis compared to degradation. Furthermore, the pathways involving extracellular matrix degradation through metalloproteinase-2 have also been shown to promote extracellular matrix synthesis. Shen et al. identified a dual role of metalloproteinase-2 in mice and also showed increased susceptibility to TAA due to metalloproteinase-2 deficiency (20). This shows that TGFB is essential in maintaining extracellular matrix stability and the defects in this signalling pathway are most prominent in the thoracic aorta as it has the greatest amount of extracellular matrix. However, dysregulation of TGFB signalling had divergent results, with both a protective and harmful role demonstrated in thoracic aorta pathology. Increased levels of TGFB have been associated with aggravating thoracic aorta pathology, as direct neutralization of TGF-B using antibodies showed reduced dilation in the ascending aorta (21). Interestingly, TGFB appears to exert different roles in the different cell types. Angelov et al. demonstrated that smooth muscle specific but not systemic inhibition of TGFB significantly increased the risk of TAA in angiotensin-II infused mice (22). This suggests that smooth muscle cell TGFB provide a protective effect on the vessel wall, and this action is possibly due to the previously established role of TGFB to stimulate VSMC proliferation (23).

Mechanics of the thoracic aorta

In order to understand the physical factors that lead to the formation of TAAD, it is important to understand mechanics of the thoracic aorta in health. Aortic tissue has several key physical properties that allow it to accommodate the pressures relayed through ventricular systole.

First, it has a non-linear stress–strain relationship at higher load levels, possibly mediated by collagen fibres (Fig. 2). Lower load levels demonstrate a nearly linear relationship between these two domains, mediated by elastin (24). Stress can be within the longitudinal or circular axis. There has been an observed difference in longitudinal stress along the path of the thoracic aorta, highest around the aortic arch and declining along the descending aorta. Secondly, aortic tissue has been demonstrated to increase in stiffness with increasing load. These properties may be exerted due to glycosaminoglycans (GAG), as research in porcine tissue treated with GAG removal showed quicker rates of stiffening in response to escalating load (25). Tissue from the thoracic aorta is pseudoelastic, in that there are different stress–strain patterns during loading and unloading. The difference can be reduced by repeating this process (i.e. conditioning tissue), however, it is suggested that this property is not demonstrated by human aortic tissue in vivo (26).

Figure 2
Figure 2

Stress–strain relationships in the thoracic aorta. The solid line depicts the natural relationship modelled in vivo. The dotted line depicts the relationship when collagen content is reduced.

Citation: Vascular Biology 3, 1; 10.1530/VB-20-0015

Aneurysmal tissue has several physical properties that are different to healthy aortic tissue. It has been demonstrated that aneurysmal specimens are stiffer in the longitudinal and circumferential dimensions compared to controls (27), however, this is inconsistent across the evidence base (28, 29). Strength and stiffness may be more pronounced circumferentially (29), possibly associated with increased deposition of collagen fibres in this direction (30). It is also suggested that there is concomitant decrease in elastin (31).

Physical forces aside from longitudinal and circumferential stress may play a part in aortic tissue remodelling. Combining ex vivo data with computational models, Witzenburg et al. demonstrated very low strength of porcine ascending aortas to radial shear, particularly in response to repeated loading (32). This could suggest an overlooked aspect of dissection.

Ability of the aorta to store and deploy energy is key to transmitting pressure from the left ventricle and driving perfusion to tissues. This property can be examined through tensile testing. Evidence suggests that a quick rate of energy loss is associated with failure of aortic tissue to withstand stress, predisposing it to dissection and aneurysms (33). The content and orientation of elastin in murine aortic tissue was found to be a strong predictor of energy storage (34). However, this finding was not replicated in a study comparing diseased murine tissue to controls (35).

The best example of these processes in action involve aneurysms caused by bicuspid aortic valve disease. Bicuspid valves differ from their counterparts with regard to number of leaflets (two vs three) and annular geometry (oval vs circular) (36). These alterations can lead to uneven sheer stress of systolic blood flow, which predisposes to aortic dilation and aneurysm formation at the root (37).

While ex vivo testing provides important information and context to link biological components with mechanical properties, inconsistencies in the evidence base suggest multiple factors may be responsible for aortic tissue failure. Furthermore, in vivo testing combined with computational fluid dynamics may be more beneficial for risk stratification and clinical decision making.

Genetic predisposition to thoracic aorta disease

TAA and TAD can be caused by syndromic and non-syndromic genetic factors.

Genetic syndromes

Marfan syndrome (MFS) is an autosomal dominant connective tissues disorder caused by mutations in the FBN1 gene, which codes for fibrillin-1. Fibrillin-1 is a significant component of the extracellular matrix, hence Marfan’s syndrome has been associated with an increased risk in thoracic aortic disease. Furthermore, deficiency in fibrillin-1 leads to the dysregulation of TGFB expression, which was thought to be the cause of thoracic aorta malformation. However, as described earlier the precise role of TGFB is controversial, and Marfan’s syndrome has not been associated with an increased expression of bioactive TGFB (38). Nolasca et al. recently identified another potential mechanism to explain the impaired smooth muscle force observed in Marfan’s syndrome (39). Furthermore, VSMC of MFS mice demonstrated a phenotype switch to mesenchymal-like cells, which resulted in impaired traction forces and a dampened force response to stiffer substrates (39). This further affirms the plasticity of the cells in the thoracic wall and its contributions to vascular disease.

Vascular Ehlers–Danlos syndrome (EDS) is another connective tissue disorder commonly associated with thoracic aorta disease. EDS type IV is an autosomal dominant pathology that is caused by a defective type III procollagen gene (COL3A1) that primarily affects the ECM of the heart and vasculature (40). Type III collagen predominates in the tunica adventitia, hence defective synthesis leads to increased fragility of the vessel, which is most prominent in the thoracic aorta. MRI measurements of the ascending aorta of EDS patients revealed a small incidence of enlarged ascending aortas without the formation of aortic aneurysms (41). Overall, the mutant type III collagen reduces stiffness of the adventitia and leads to widening of the aorta.

Loey–Dietz syndrome (LDS) is an autosomal dominant connective tissue disease that shares features with MFS and EDS. There are five types (types 1–5), caused by mutations in TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3, respectively (42). Although autosomal dominant, at least 75% of patients have a de novo mutation and are the first in their family to manifest the disease (42). These mutations interfere with cell signalling pathways modulated by TGFB (discussed earlier). Patients with LDS present with aneurysms of the aorta which are particularly susceptible to dissection and the only available therapy is surgical treatment and regular surveillance.

Non-syndromic genetic predisposition

Non-syndromic causes of TAAD are confined to the aorta and do not have other systemic abnormalities. Non-syndromic causes account for 95% of all TAADs and can be further subdivided into familial and non-familial (also known as sporadic) (43). Familial non-syndromic TAADs refers to the instance when one or more family member is also diagnosed with TAAD (44). Research continues to identify genetic causes of familial TAADs, as 21% of patients have a positive family history of the condition. Interestingly, 21% appears to be an underestimate as many family members do not undergo the routine imaging to identify non-symptomatic aneurysms (43). In contrast, it was previously thought that sporadic non-syndromic TAADs are solely degenerative mediated. However, recent research suggests that there is also an underlying genetic cause in sporadic non-syndromic TAADs most likely due to variably penetrant gene expression (45).

ACTA2 encodes an isoform specific to SMC of α-actin, which polymerises to form thin filaments of the contractile unit. Mutations in ACTA2 disrupts the amino acid arrangement in the subdomains of the actin, which alters the gross structure of the actin monomer. This leads to dysfunctional contraction of SMCs, manifesting as multisystemic smooth muscle dysfunction syndrome, which contributes to the pathogenesis of TAAD (40). Furthermore, Lu et al. demonstrated that the structurally altered actin monomer showed impaired interaction with myosin, unstable filament formations and an increase the number of actin monomer (46). The multiple defects observed suggest that mutant actin will decrease contractility of SMC in response to pulse pressure. Hence, ACTA2 mutations have the most pronounced effect in the thoracic aorta which is sensitive to pulse pressure and requires a highly responsive vessel wall.

Multifactorial origin of thoracic aortic disease

There is a complex interplay between biological, mechanical and genetic factors that may cause thoracic aortic disease. The composition of aortic tissue provides it with inherent physical factors that allow it to accommodate and transmit pressures from the left ventricular outflow tract and maintain perfusion to the whole body. This is governed by chemical signalling and the function of these proteins are influenced by genetic factors.

Stress across aortic walls is conventionally thought to be exerted longitudinally and circumferentially. The relationship has been demonstrated to be non-linear, particularly at higher load levels. Longitudinal stress may differ more markedly than circumferential along the course of the thoracic aorta, and this is related to the reduction in elastin deposition along its length. The orientation of collagen fibres may also play an important role in stiffness and the stress–strain relationship of aortic tissue. Genetic disorders such as EDS interfere with the synthesis of collagen, which affects the ability of the thoracic aorta to withstand large pressures and predispose it to aneurysms and dissections due to wall weakness.

SMC play an integral role in the dynamic response to change in pressures within the thoracic aorta and they are sensitive to neural input. Modulating the stress–strain relationship, loading and unloading is critical to ensure integrity of the vessel and maintain perfusion. Mutations in components such as actin and myosin have been demonstrated in vivo to reduce contractility of these cells. The factors governing genetic syndromes such as abnormal elastin, tone and signalling can lead to maladaptive mechanotransduction which ultimately lead to a failure in aortic tissue to cope with wall stress. Since the genetic basis of TAAD is poorly understood, there are likely numerous genetic defects that affect smooth muscle cells, collagen and elastin to alter the strength and durability of tissue.

Most studies investigating thoracic aorta physiology usually analyse only one factor such as cell phenotype, which makes examining the interplay between all bio-chemo-mechanical factors difficult. However, there are a few experiments which have studied at least two factors and provide some insight on the combined effect of these factors. For example, Yamashiro et al. analysed solid mechanics in the context of extracellular matrix changes and determined that loss of elastic fibres in the thoracic wall leads to dysfunction in the mechanosensing of SMC (47). Atkins et al. investigated the effect of disruption in haemodynamics and its influence on the structure of the vessel wall. The porcine models demonstrated that disruptions in fluid dynamics influence chemical pathways, such as metalloproteinase 2, and directly mediatemedial degradation which contributes to TAA formation (48). These limited studies provide an insight on how the bio-chemo-mechanics factor are vital in normal physiology and that disruption in one can affect other factors and contribute to disease.

It is worth noting that the most prominent risk factor noted in patients with aneurysm or dissection is hypertension, highlighting the influence of lifestyle factors and interplay with biological and mechanical factors that affect integrity of the aorta. Bersi et al. examined the extracellular matrix and biomechanical difference of the thoracic aorta in hypertensive mice models to understand the varying susceptibility to disease in different sections of the aorta (49). The hypertensive models demonstrated disrupted intrinsic material stiffness in the intra mural cells of the ascending aorta, which leads to aneurysmal dilation. Additionally, the descending aorta showed excess fibrosis due to mechanical stress-initiated and inflammation-driven remodelling.

Screening programmes

There are no formal screening programmes for TAAs, possibly due to relative infrequency. A systematic review examined the evidence on the utility of screening for TAA in patients with giant cell arteritis. They reported significantly increased risk in these patients compared to controls. However, up to 5–10 patients would need imaging to detect a previously unknown aneurysm or dissection (50). Research investigating the value of genetic screening in patients with TAA or TAD found nearly a quarter had mutations of unknown significance in the 21 gene panel set (48).

Screening programmes may be of limited clinical utility in the general population but may be of use in at-risk patients. Additionally, deciding on an appropriate modality that is sensitive, specific and cost-effective is crucial to the success of any prospective programme. Commonly used imaging techniques (such as ultrasound) could be employed to track the strain in TAAs and aortic tissue stiffness, which have been subsequently validated (49, 50). Emerging technologies include 4D ultrasound, which can estimate strain using time-resolved 3D images. They have been used to good effect in estimating animal aortic aneurysm strain (51). Further research is needed to ensure an accessible, sensitive technique is chosen to enable creation of a feasible screening programme.

A major issue faced by clinicians in the management of TAAD is the capacity to determine which patient with an aneurysm will dissect or rupture. Currently, aortic diameter is measured to predict the aneurysm risk, however, it fails to detect all potential TAADs even in patient with a family history of TAAD (52). This emphasizes the need to find new biomarkers to help stratify risk in patients with a TAA. A recent study identified that elevated and persistent levels CRP, IL6 and TNF were as associated with progression of TAAD. The changing pattern of CRP could potentially be used as a marker of diagnosis and prophylactic treatment of complications (53).

Future research

There is a plethora of studies exploring one factor to assess its mechanism on the context of the thoracic aorta. Future studies should aim to combine the results of different experiments in a multifactorial computational model to assess the bio-chemo-mechanics of the thoracic aorta. Current studies only usually only focus on one factor, such as mechanics or biology and do not provide insight on how they rely on each other and contribute towards the pathological mechanism of thoracic disease. Additionally, bio-chemo-mechanical role of other components of the thoracic aorta also require further attention. For example, the role of proteoglycan in disease progression in the thoracic aorta is unclear and warrants further investigation, as they appear to be important in the signalling pathways of the thoracic aorta (50). TGFB is another yet controversial cytokine as its signalling pathway in disease has provided divergent results. Hence, future research should also aim to use more robust methods to investigate the role of TGFB. For example, many studies in the past have used pSmad 2 as a surrogate marker of TGFB. However, this has its own caveats as other pathways independent of TGFB have also shown to activate SMAD2 (36). Therefore, careful experimental designs and objective interpretation are required for future studies to tackle the wide range of disparities.

At present, clinical prediction of the risk of aneurysmal rupture is confined to aortic diameter. This metric is unreliable and shows great variation between individuals, therefore there is a need to determine biomarkers that are correlated with aneurysmal growth and risk of rupture. This will allow appropriate risk factor stratification and more accurate clinical decision making.

Summary and conclusion

Thoracic aortic aneurysms and dissections are serious albeit rare diseases that can result in high mortality if not detected and managed appropriately. The pathophysiology is poorly understood and has several factors in play. Smooth muscle cells and the composition of collagen and elastin helps mediate key mechanical properties that allow the thoracic aorta to withstand and transmit large pressures, however, remodelling is poor and dysfunctional processes can lead to tissue failure. Genetic syndromes can lead to defects in signalling proteins responsible for muscle contraction or connective tissue composition, thereby leading to inherent weakness. The impact of hypertension (which has genetic and environmental influences) is considerable in development of TAA and TADs, highlighting the need for research that considers multiple factors in studying pathophysiology.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

S I and A R conducted the literature search, wrote the first draft of the manuscript, was involved in editing and formatting the final manuscript. A H conceived the review, supervised data collection and writing of the manuscript.

References

  • 1

    Olsson C, Thelin S, Ståhle E, Ekbom A & Granath F Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in a nationwide population-based study of more than 14 000 cases from 1987 to 2002. Circulation 2006 114 26112618. (https://doi.org/10.1161/CIRCULATIONAHA.106.630400)

    • Search Google Scholar
    • Export Citation
  • 2

    Criado FJ Aortic dissection: a 250-year perspective. Texas Heart Institute Journal 2011 38 694700.

  • 3

    Golledge J & Eagle KA Acute aortic dissection. Lancet 2008 372 5566. (https://doi.org/10.1016/S0140-6736(0860994-0)

  • 4

    Ruddy JM, Jones JA & Ikonomidis JS Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin. Progress in Cardiovascular Diseases 2013 56 6873. (https://doi.org/10.1016/j.pcad.2013.04.002)

    • Search Google Scholar
    • Export Citation
  • 5

    Humphrey JD, Schwartz MA, Tellides G & Milewicz DM Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circulation Research 2015 116 14481461. (https://doi.org/10.1161/CIRCRESAHA.114.304936)

    • Search Google Scholar
    • Export Citation
  • 6

    Jana S, Hu M, Shen M & Kassiri Z Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm. Experimental & Molecular Medicine 2019 51 115. (https://doi.org/10.1038/s12276-019-0286-3)

    • Search Google Scholar
    • Export Citation
  • 7

    Cebull HL, Rayz VL & Goergen CJ Recent advances in biomechanical characterization of thoracic aortic aneurysms. Frontiers in Cardiovascular Medicine 2020 7 75. (https://doi.org/10.3389/fcvm.2020.00075)

    • Search Google Scholar
    • Export Citation
  • 8

    Hallmann R, Horn N, Selg M, Wendler O, Pausch F & Sorokin LM Expression and function of laminins in the embryonic and mature vasculature. Physiological Reviews 2005 85 9791000. (https://doi.org/10.1152/physrev.00014.2004)

    • Search Google Scholar
    • Export Citation
  • 9

    Emmott A, Garcia J, Chung J, Lachapelle K, El-Hamamsy I, Mongrain R, Cartier R & Leask RL Biomechanics of the ascending thoracic aorta: a clinical perspective on engineering data. Canadian Journal of Cardiology 2016 32 3547. (https://doi.org/10.1016/j.cjca.2015.10.015)

    • Search Google Scholar
    • Export Citation
  • 10

    Godwin ARF, Singh M, Lockhart-Cairns MP, Alanazi YF, Cain SA & Baldock C The role of fibrillin and microfibril binding proteins in elastin and elastic fibre assembly. Matrix Biology 2019 84 1730. (https://doi.org/10.1016/j.matbio.2019.06.006)

    • Search Google Scholar
    • Export Citation
  • 11

    Sawada H, Rateri DL, Moorleghen JJ, Majesky MW & Daugherty A Smooth muscle cells derived from second heart field and cardiac neural crest reside in spatially distinct domains in the media of the ascending aorta - brief report. Arteriosclerosis, Thrombosis, & Vascular Biology 2017 37 17221726. (https://doi.org/10.1161/ATVBAHA.117.309599)

    • Search Google Scholar
    • Export Citation
  • 12

    Isselbacher EM Thoracic and abdominal aortic aneurysms. Circulation 2005 111 816828. (https://doi.org/10.1161/01.CIR.0000154569.08857.7A)

    • Search Google Scholar
    • Export Citation
  • 13

    Cocciolone AJ, Hawes JZ, Staiculescu MC, Johnson EO, Murshed M & Wagenseil JE Elastin, arterial mechanics, and cardiovascular disease. American Journal of Physiology. Heart and Circulatory Physiology 2018 315 H189H205. (https://doi.org/10.1152/ajpheart.00087.2018)

    • Search Google Scholar
    • Export Citation
  • 14

    Tonar Z, Tomášek P, Loskot P, Janáček J, Králíčková M & Witter K Vasa vasorum in the tunica media and tunica adventitia of the porcine aorta. Annals of Anatomy 2016 205 2236. (https://doi.org/10.1016/j.aanat.2016.01.008)

    • Search Google Scholar
    • Export Citation
  • 15

    Federspiel JM, Tschernig T, Laschke MW, Wagenpfeil S, Schnabel P & Schäfers HJ The vasa vasorum reach deep into the human thoracic aorta. Annals of Anatomy 2019 225 5456. (https://doi.org/10.1016/j.aanat.2019.06.001)

    • Search Google Scholar
    • Export Citation
  • 16

    Gasser TC, Ogden RW & Holzapfel GA Hyperelastic modelling of arterial layers with distributed collagen fibre orientations. Journal of the Royal Society, Interface 2006 3 1535. (https://doi.org/10.1098/rsif.2005.0073)

    • Search Google Scholar
    • Export Citation
  • 17

    Sandison ME, Dempster J & McCarron JG The transition of smooth muscle cells from a contractile to a migratory, phagocytic phenotype: direct demonstration of phenotypic modulation. Journal of Physiology 2016 594 61896209. (https://doi.org/10.1113/JP272729)

    • Search Google Scholar
    • Export Citation
  • 18

    Karimi A & Milewicz DM Structure of the elastin-contractile units in the thoracic aorta and how genes that cause thoracic aortic aneurysms and dissections disrupt this structure. Canadian Journal of Cardiology 2016 32 2634. (https://doi.org/10.1016/j.cjca.2015.11.004)

    • Search Google Scholar
    • Export Citation
  • 19

    Leloup AJA, Van Hove CE, De Moudt S, De Meyer GRY, De Keulenaer GW & Fransen P Vascular smooth muscle cell contraction and relaxation in the isolated aorta: a critical regulator of large artery compliance. Physiological Reports 2019 7 e13934. (https://doi.org/10.14814/phy2.13934)

    • Search Google Scholar
    • Export Citation
  • 20

    Shen M, Lee J, Basu R, Sakamuri SS, Wang X, Fan D & Kassiri Z Divergent roles of matrix metalloproteinase 2 in pathogenesis of thoracic aortic aneurysm. Arteriosclerosis, Thrombosis, & Vascular Biology 2015 35 888898. (https://doi.org/10.1161/ATVBAHA.114.305115)

    • Search Google Scholar
    • Export Citation
  • 21

    King VL, Lin AY, Kristo F, Anderson TJ, Ahluwalia N, Hardy GJ, Owens AP, Howatt DA, Shen D & Tager AM et al. Interferon-γ and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture. Circulation 2009 119 426435. (https://doi.org/10.1161/CIRCULATIONAHA.108.785949)

    • Search Google Scholar
    • Export Citation
  • 22

    Angelov SN, Hu JH, Wei H, Airhart N, Shi M & D’Ichek DA TGF-β (transforming growth factor-β) signaling protects the thoracic and abdominal aorta from angiotensin iiinduced pathology by distinct mechanisms. Arteriosclerosis, Thrombosis, & Vascular Biology 2017 37 21022113. (https://doi.org/10.1161/ATVBAHA.117.309401)

    • Search Google Scholar
    • Export Citation
  • 23

    Suwanabol PA, Seedial SM, Shi X, Zhang F, Yamanouchi D, Roenneburg D, Liu B & Kent KC Transforming growth factor-β increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinases pathways. Journal of Vascular Surgery 2012 56 446–454. (https://doi.org/10.1016/j.jvs.2011.12.038)

    • Search Google Scholar
    • Export Citation
  • 24

    Elefteriades JA Thoracic aortic aneurysm: reading the enemy’s playbook. World Journal of Surgery 2008 32 366374. (https://doi.org/10.1007/s00268-007-9398-3)

    • Search Google Scholar
    • Export Citation
  • 25

    Sherifova S & Holzapfel GA Biochemomechanics of the thoracic aorta in health and disease. Progress in Biomedical Engineering 2 032002. (https://doi.org/10.1088/2516-1091/ab9a29)

    • Search Google Scholar
    • Export Citation
  • 26

    Mattson JM, Turcotte R & Zhang Y Glycosaminoglycans contribute to extracellular matrix fiber recruitment and arterial wall mechanics. Biomechanics & Modeling in Mechanobiology 2017 16 213225. (https://doi.org/10.1007/s10237-016-0811-4)

    • Search Google Scholar
    • Export Citation
  • 27

    Weisbecker H, Viertler C, Pierce DM & Holzapfel GA The role of elastin and collagen in the softening behavior of the human thoracic aortic media. Journal of Biomechanics 2013 46 18591865. (https://doi.org/10.1016/j.jbiomech.2013.04.025)

    • Search Google Scholar
    • Export Citation
  • 28

    Iliopoulos DC, Deveja RP, Kritharis EP, Perrea D, Sionis GD, Toutouzas K, Stefanadis C & Sokolis DP Regional and directional variations in the mechanical properties of ascending thoracic aortic aneurysms. Medical Engineering & Physics 2009 31 19. (https://doi.org/10.1016/j.medengphy.2008.03.002)

    • Search Google Scholar
    • Export Citation
  • 29

    Sokolis DP, Krithais EP, Giagini AT, Lampropoulos KM, Papadodima SA & Iliopoulos DC Biomechanical response of ascending thoracic aortic aneurysms: association with structural remodelling. Computer Methods in Biomechanics & Biomedical Engineering 2012 15 231248. (https://doi.org/10.1080/10255842.2010.522186)

    • Search Google Scholar
    • Export Citation
  • 30

    Shah SB, Witzenburg C, Hadi MF, Wagner HP, Goodrich JM, Alford PW & Barocas VH Prefailure and failure mechanics of the porcine ascending thoracic aorta: experiments and a multiscale model. Journal of Biomechanical Engineering 2014 136 021028.(https://doi.org/10.1115/1.4026443:24402447)

    • Search Google Scholar
    • Export Citation
  • 31

    Babu AR, Byju AG & Gundiah N Biomechanical properties of human ascending thoracic aortic dissections. Journal of Biomechanical Engineering 2015 137 081013. (https://doi.org/10.1115/1.4030752)

    • Search Google Scholar
    • Export Citation
  • 32

    Witzenburg CM, Dhume RY, Shah SB, Korenczuk CE, Wagner HP, Alford PW & Barocas VH Failure of the porcine ascending aorta: multidirectional experiments and a unifying microstructural model. Journal of Biomechanical Engineering 2017 139 031005. (https://doi.org/10.1115/1.4035264)

    • Search Google Scholar
    • Export Citation
  • 33

    Chung J, Lachapelle K, Wener E, Cartier R, De Varennes B, Fraser R & Leask RL Energy loss, a novel biomechanical parameter, correlates with aortic aneurysm size and histopathologic findings. Journal of Thoracic and Cardiovascular Surgery 2014 148 10821088; discussion 1088. (https://doi.org/10.1016/j.jtcvs.2014.06.021)

    • Search Google Scholar
    • Export Citation
  • 34

    Kim J, Staiculescu MC, Cocciolone AJ, Yanagisawa H, Mecham RP & Wagenseil JE Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. Journal of Biomechanics 2017 61 199207. (https://doi.org/10.1016/j.jbiomech.2017.07.011)

    • Search Google Scholar
    • Export Citation
  • 35

    Bellini C, Kristofik NJ, Bersi MR, Kyriakides TR & Humphrey JD A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. Journal of the Mechanical Behavior of Biomedical Materials 2017 71 397406. (https://doi.org/10.1016/j.jmbbm.2017.01.045)

    • Search Google Scholar
    • Export Citation
  • 36

    Bäck M, Gasser TC, Michel J & Caligiuri G Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovascular Research 2013 99 232241. (https://doi.org/10.1093/cvr/cvt040)

    • Search Google Scholar
    • Export Citation
  • 37

    Yap CH, Saikrishnan N, Tamilselvan G, Vasilyev N & Yoganathan AP The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface. American Journal of Physiology. Heart & Circulatory Physiology 2012 303 H721H731. (https://doi.org/10.1152/ajpheart.00829.2011)

    • Search Google Scholar
    • Export Citation
  • 38

    Daugherty A, Chen Z, Sawada H, Rateri DL & Sheppard MB Transforming growth factor-β in thoracic aortic aneurysms: good, bad, or irrelevant? Journal of the American Heart Association 2017 6. (https://doi.org/10.1161/JAHA.116.005221)

    • Search Google Scholar
    • Export Citation
  • 39

    Nolasco P, Fernandes CG, Ribeiro-Silva JC, Oliveira PVS, Sacrini M, de Brito IV, De Bessa TC, Pereira LV, Tanaka LY & Alencar A et al. Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan syndrome mice. Biochimica et Biophysica Acta. Molecular Basis of Disease 2020 1866 165587. (https://doi.org/10.1016/j.bbadis.2019.165587)

    • Search Google Scholar
    • Export Citation
  • 40

    Harky A, Fan KS & Fan KH The genetics and biomechanics of thoracic aortic diseases. Vascular Biology 2019 1 R13R25. (https://doi.org/10.1530/VB-19-0027)

    • Search Google Scholar
    • Export Citation
  • 41

    Kerwin W, Pepin M, Mitsumori L, Yarnykh V, Schwarze U & Byers P MRI of great vessel morphology and function in Ehlers-Danlos syndrome type IV. International Journal of Cardiovascular Imaging 2008 24 519528. (https://doi.org/10.1007/s10554-007-9283-z)

    • Search Google Scholar
    • Export Citation
  • 42

    Conditions G Loeys-Dietz Syndrome: MedlinePlus Genetics 2020 [Internet] Medlineplus.gov [cited 23 December 2020]. (available at: https://medlineplus.gov/genetics/condition/loeys-dietz-syndrome/).

    • Search Google Scholar
    • Export Citation
  • 43

    Faggion Vinholo T, Zafar MA, Ziganshin BA & Elefteriades JA Nonsyndromic thoracic aortic aneurysms and dissections—is screening possible? Seminars in Thoracic & Cardiovascular Surgery 2019 31 628634. (https://doi.org/10.1053/j.semtcvs.2019.05.035)

    • Search Google Scholar
    • Export Citation
  • 44

    Ostberg NP, Zafar MA, Ziganshin BA & Elefteriades JA The genetics of thoracic aortic aneurysms and dissection: a clinical perspective. Biomolecules 2020 10. (https://doi.org/10.3390/biom10020182)

    • Search Google Scholar
    • Export Citation
  • 45

    Guo DC, Hostetler EM, Fan Y, Kulmacz RJ, Zhang DGenTAC Investigators, Nickerson DA, Leal SM, LeMaire SA & Regalado ES et al. Heritable thoracic aortic disease genes in sporadic aortic dissection. Journal of the American College of Cardiology 2017 70 27282730. (https://doi.org/10.1016/j.jacc.2017.09.1094)

    • Search Google Scholar
    • Export Citation
  • 46

    Lu H, Fagnant PM, Bookwalter CS, Joel P & Trybus KM Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin. Proceedings of the National Academy of Sciences of the United States of America 2015 112 E4168E4177. (https://doi.org/10.1073/pnas.1507587112)

    • Search Google Scholar
    • Export Citation
  • 47

    Yamashiro Y, Papke CL, Kim J, Ringuette LJ, Zhang QJ, Liu ZP, Mirzaei H, Wagenseil JE, Davis EC & Yanagisawa H Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. Science Signaling 2015 8 ra105. (https://doi.org/10.1126/scisignal.aab3141)

    • Search Google Scholar
    • Export Citation
  • 48

    Atkins SK, Cao K, Rajamannan NM & Sucosky P Bicuspid aortic valve hemodynamics induces abnormal medial remodeling in the convexity of porcine ascending aortas. Biomechanics & Modeling in Mechanobiology 2014 13 12091225. (https://doi.org/10.1007/s10237-014-0567-7)

    • Search Google Scholar
    • Export Citation
  • 49

    Bersi MR, Khosravi R, Wujciak AJ, Harrison DG & Humphrey JD Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension. Journal of the Royal Society, Interface 2017 14. (https://doi.org/10.1098/rsif.2017.0327)

    • Search Google Scholar
    • Export Citation
  • 50

    Mackie SL, Hensor EMA, Morgan AW & Pease CT Should i send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta-analysis. Annals of the Rheumatic Diseases 2014 73 143148. (https://doi.org/10.1136/annrheumdis-2012-202145)

    • Search Google Scholar
    • Export Citation
  • 51

    Ziganshin BA, Bailey AE, Coons C, Dykas D, Charilaou P, Tanriverdi LH, Liu L, Tranquilli M, Bale AE & Elefteriades JA Routine genetic testing for thoracic aortic aneurysm and dissection in a clinical setting. Annals of Thoracic Surgery 2015 100 1604161 1. (https://doi.org/10.1016/j.athoracsur.2015.04.106)

    • Search Google Scholar
    • Export Citation
  • 52

    Hannuksela M, Stattin EL, Johansson B & Carlberg B Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential carriers of the disease. Aorta 2015 3 18. (https://doi.org/10.12945/j.aorta.2015.14-052)

    • Search Google Scholar
    • Export Citation
  • 53

    Gu J, Hu J, Zhang HW, Xiao ZH, Fang Z, Qian H, Zhong MH, Guo YQ, Zhang EY & Shi YK et al. Time-dependent changes of plasma inflammatory biomarkers in type A aortic dissection patients without optimal medical management. Journal of Cardiothoracic Surgery 2015 10 3. (https://doi.org/10.1186/s13019-014-0199-0)

    • Search Google Scholar
    • Export Citation

 

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    Layers of the thoracic aorta.

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    Stress–strain relationships in the thoracic aorta. The solid line depicts the natural relationship modelled in vivo. The dotted line depicts the relationship when collagen content is reduced.

  • 1

    Olsson C, Thelin S, Ståhle E, Ekbom A & Granath F Thoracic aortic aneurysm and dissection: increasing prevalence and improved outcomes reported in a nationwide population-based study of more than 14 000 cases from 1987 to 2002. Circulation 2006 114 26112618. (https://doi.org/10.1161/CIRCULATIONAHA.106.630400)

    • Search Google Scholar
    • Export Citation
  • 2

    Criado FJ Aortic dissection: a 250-year perspective. Texas Heart Institute Journal 2011 38 694700.

  • 3

    Golledge J & Eagle KA Acute aortic dissection. Lancet 2008 372 5566. (https://doi.org/10.1016/S0140-6736(0860994-0)

  • 4

    Ruddy JM, Jones JA & Ikonomidis JS Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin. Progress in Cardiovascular Diseases 2013 56 6873. (https://doi.org/10.1016/j.pcad.2013.04.002)

    • Search Google Scholar
    • Export Citation
  • 5

    Humphrey JD, Schwartz MA, Tellides G & Milewicz DM Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circulation Research 2015 116 14481461. (https://doi.org/10.1161/CIRCRESAHA.114.304936)

    • Search Google Scholar
    • Export Citation
  • 6

    Jana S, Hu M, Shen M & Kassiri Z Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm. Experimental & Molecular Medicine 2019 51 115. (https://doi.org/10.1038/s12276-019-0286-3)

    • Search Google Scholar
    • Export Citation
  • 7

    Cebull HL, Rayz VL & Goergen CJ Recent advances in biomechanical characterization of thoracic aortic aneurysms. Frontiers in Cardiovascular Medicine 2020 7 75. (https://doi.org/10.3389/fcvm.2020.00075)

    • Search Google Scholar
    • Export Citation
  • 8

    Hallmann R, Horn N, Selg M, Wendler O, Pausch F & Sorokin LM Expression and function of laminins in the embryonic and mature vasculature. Physiological Reviews 2005 85 9791000. (https://doi.org/10.1152/physrev.00014.2004)

    • Search Google Scholar
    • Export Citation
  • 9

    Emmott A, Garcia J, Chung J, Lachapelle K, El-Hamamsy I, Mongrain R, Cartier R & Leask RL Biomechanics of the ascending thoracic aorta: a clinical perspective on engineering data. Canadian Journal of Cardiology 2016 32 3547. (https://doi.org/10.1016/j.cjca.2015.10.015)

    • Search Google Scholar
    • Export Citation
  • 10

    Godwin ARF, Singh M, Lockhart-Cairns MP, Alanazi YF, Cain SA & Baldock C The role of fibrillin and microfibril binding proteins in elastin and elastic fibre assembly. Matrix Biology 2019 84 1730. (https://doi.org/10.1016/j.matbio.2019.06.006)

    • Search Google Scholar
    • Export Citation
  • 11

    Sawada H, Rateri DL, Moorleghen JJ, Majesky MW & Daugherty A Smooth muscle cells derived from second heart field and cardiac neural crest reside in spatially distinct domains in the media of the ascending aorta - brief report. Arteriosclerosis, Thrombosis, & Vascular Biology 2017 37 17221726. (https://doi.org/10.1161/ATVBAHA.117.309599)

    • Search Google Scholar
    • Export Citation
  • 12

    Isselbacher EM Thoracic and abdominal aortic aneurysms. Circulation 2005 111 816828. (https://doi.org/10.1161/01.CIR.0000154569.08857.7A)

    • Search Google Scholar
    • Export Citation
  • 13

    Cocciolone AJ, Hawes JZ, Staiculescu MC, Johnson EO, Murshed M & Wagenseil JE Elastin, arterial mechanics, and cardiovascular disease. American Journal of Physiology. Heart and Circulatory Physiology 2018 315 H189H205. (https://doi.org/10.1152/ajpheart.00087.2018)

    • Search Google Scholar
    • Export Citation
  • 14

    Tonar Z, Tomášek P, Loskot P, Janáček J, Králíčková M & Witter K Vasa vasorum in the tunica media and tunica adventitia of the porcine aorta. Annals of Anatomy 2016 205 2236. (https://doi.org/10.1016/j.aanat.2016.01.008)

    • Search Google Scholar
    • Export Citation
  • 15

    Federspiel JM, Tschernig T, Laschke MW, Wagenpfeil S, Schnabel P & Schäfers HJ The vasa vasorum reach deep into the human thoracic aorta. Annals of Anatomy 2019 225 5456. (https://doi.org/10.1016/j.aanat.2019.06.001)

    • Search Google Scholar
    • Export Citation
  • 16

    Gasser TC, Ogden RW & Holzapfel GA Hyperelastic modelling of arterial layers with distributed collagen fibre orientations. Journal of the Royal Society, Interface 2006 3 1535. (https://doi.org/10.1098/rsif.2005.0073)

    • Search Google Scholar
    • Export Citation
  • 17

    Sandison ME, Dempster J & McCarron JG The transition of smooth muscle cells from a contractile to a migratory, phagocytic phenotype: direct demonstration of phenotypic modulation. Journal of Physiology 2016 594 61896209. (https://doi.org/10.1113/JP272729)

    • Search Google Scholar
    • Export Citation
  • 18

    Karimi A & Milewicz DM Structure of the elastin-contractile units in the thoracic aorta and how genes that cause thoracic aortic aneurysms and dissections disrupt this structure. Canadian Journal of Cardiology 2016 32 2634. (https://doi.org/10.1016/j.cjca.2015.11.004)

    • Search Google Scholar
    • Export Citation
  • 19

    Leloup AJA, Van Hove CE, De Moudt S, De Meyer GRY, De Keulenaer GW & Fransen P Vascular smooth muscle cell contraction and relaxation in the isolated aorta: a critical regulator of large artery compliance. Physiological Reports 2019 7 e13934. (https://doi.org/10.14814/phy2.13934)

    • Search Google Scholar
    • Export Citation
  • 20

    Shen M, Lee J, Basu R, Sakamuri SS, Wang X, Fan D & Kassiri Z Divergent roles of matrix metalloproteinase 2 in pathogenesis of thoracic aortic aneurysm. Arteriosclerosis, Thrombosis, & Vascular Biology 2015 35 888898. (https://doi.org/10.1161/ATVBAHA.114.305115)

    • Search Google Scholar
    • Export Citation
  • 21

    King VL, Lin AY, Kristo F, Anderson TJ, Ahluwalia N, Hardy GJ, Owens AP, Howatt DA, Shen D & Tager AM et al. Interferon-γ and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture. Circulation 2009 119 426435. (https://doi.org/10.1161/CIRCULATIONAHA.108.785949)

    • Search Google Scholar
    • Export Citation
  • 22

    Angelov SN, Hu JH, Wei H, Airhart N, Shi M & D’Ichek DA TGF-β (transforming growth factor-β) signaling protects the thoracic and abdominal aorta from angiotensin iiinduced pathology by distinct mechanisms. Arteriosclerosis, Thrombosis, & Vascular Biology 2017 37 21022113. (https://doi.org/10.1161/ATVBAHA.117.309401)

    • Search Google Scholar
    • Export Citation
  • 23

    Suwanabol PA, Seedial SM, Shi X, Zhang F, Yamanouchi D, Roenneburg D, Liu B & Kent KC Transforming growth factor-β increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen-activated protein kinases pathways. Journal of Vascular Surgery 2012 56 446–454. (https://doi.org/10.1016/j.jvs.2011.12.038)

    • Search Google Scholar
    • Export Citation
  • 24

    Elefteriades JA Thoracic aortic aneurysm: reading the enemy’s playbook. World Journal of Surgery 2008 32 366374. (https://doi.org/10.1007/s00268-007-9398-3)

    • Search Google Scholar
    • Export Citation
  • 25

    Sherifova S & Holzapfel GA Biochemomechanics of the thoracic aorta in health and disease. Progress in Biomedical Engineering 2 032002. (https://doi.org/10.1088/2516-1091/ab9a29)

    • Search Google Scholar
    • Export Citation
  • 26

    Mattson JM, Turcotte R & Zhang Y Glycosaminoglycans contribute to extracellular matrix fiber recruitment and arterial wall mechanics. Biomechanics & Modeling in Mechanobiology 2017 16 213225. (https://doi.org/10.1007/s10237-016-0811-4)

    • Search Google Scholar
    • Export Citation
  • 27

    Weisbecker H, Viertler C, Pierce DM & Holzapfel GA The role of elastin and collagen in the softening behavior of the human thoracic aortic media. Journal of Biomechanics 2013 46 18591865. (https://doi.org/10.1016/j.jbiomech.2013.04.025)

    • Search Google Scholar
    • Export Citation
  • 28

    Iliopoulos DC, Deveja RP, Kritharis EP, Perrea D, Sionis GD, Toutouzas K, Stefanadis C & Sokolis DP Regional and directional variations in the mechanical properties of ascending thoracic aortic aneurysms. Medical Engineering & Physics 2009 31 19. (https://doi.org/10.1016/j.medengphy.2008.03.002)

    • Search Google Scholar
    • Export Citation
  • 29

    Sokolis DP, Krithais EP, Giagini AT, Lampropoulos KM, Papadodima SA & Iliopoulos DC Biomechanical response of ascending thoracic aortic aneurysms: association with structural remodelling. Computer Methods in Biomechanics & Biomedical Engineering 2012 15 231248. (https://doi.org/10.1080/10255842.2010.522186)

    • Search Google Scholar
    • Export Citation
  • 30

    Shah SB, Witzenburg C, Hadi MF, Wagner HP, Goodrich JM, Alford PW & Barocas VH Prefailure and failure mechanics of the porcine ascending thoracic aorta: experiments and a multiscale model. Journal of Biomechanical Engineering 2014 136 021028.(https://doi.org/10.1115/1.4026443:24402447)

    • Search Google Scholar
    • Export Citation
  • 31

    Babu AR, Byju AG & Gundiah N Biomechanical properties of human ascending thoracic aortic dissections. Journal of Biomechanical Engineering 2015 137 081013. (https://doi.org/10.1115/1.4030752)

    • Search Google Scholar
    • Export Citation
  • 32

    Witzenburg CM, Dhume RY, Shah SB, Korenczuk CE, Wagner HP, Alford PW & Barocas VH Failure of the porcine ascending aorta: multidirectional experiments and a unifying microstructural model. Journal of Biomechanical Engineering 2017 139 031005. (https://doi.org/10.1115/1.4035264)

    • Search Google Scholar
    • Export Citation
  • 33

    Chung J, Lachapelle K, Wener E, Cartier R, De Varennes B, Fraser R & Leask RL Energy loss, a novel biomechanical parameter, correlates with aortic aneurysm size and histopathologic findings. Journal of Thoracic and Cardiovascular Surgery 2014 148 10821088; discussion 1088. (https://doi.org/10.1016/j.jtcvs.2014.06.021)

    • Search Google Scholar
    • Export Citation
  • 34

    Kim J, Staiculescu MC, Cocciolone AJ, Yanagisawa H, Mecham RP & Wagenseil JE Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. Journal of Biomechanics 2017 61 199207. (https://doi.org/10.1016/j.jbiomech.2017.07.011)

    • Search Google Scholar
    • Export Citation
  • 35

    Bellini C, Kristofik NJ, Bersi MR, Kyriakides TR & Humphrey JD A hidden structural vulnerability in the thrombospondin-2 deficient aorta increases the propensity to intramural delamination. Journal of the Mechanical Behavior of Biomedical Materials 2017 71 397406. (https://doi.org/10.1016/j.jmbbm.2017.01.045)

    • Search Google Scholar
    • Export Citation
  • 36

    Bäck M, Gasser TC, Michel J & Caligiuri G Biomechanical factors in the biology of aortic wall and aortic valve diseases. Cardiovascular Research 2013 99 232241. (https://doi.org/10.1093/cvr/cvt040)

    • Search Google Scholar
    • Export Citation
  • 37

    Yap CH, Saikrishnan N, Tamilselvan G, Vasilyev N & Yoganathan AP The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface. American Journal of Physiology. Heart & Circulatory Physiology 2012 303 H721H731. (https://doi.org/10.1152/ajpheart.00829.2011)

    • Search Google Scholar
    • Export Citation
  • 38

    Daugherty A, Chen Z, Sawada H, Rateri DL & Sheppard MB Transforming growth factor-β in thoracic aortic aneurysms: good, bad, or irrelevant? Journal of the American Heart Association 2017 6. (https://doi.org/10.1161/JAHA.116.005221)

    • Search Google Scholar
    • Export Citation
  • 39

    Nolasco P, Fernandes CG, Ribeiro-Silva JC, Oliveira PVS, Sacrini M, de Brito IV, De Bessa TC, Pereira LV, Tanaka LY & Alencar A et al. Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan syndrome mice. Biochimica et Biophysica Acta. Molecular Basis of Disease 2020 1866 165587. (https://doi.org/10.1016/j.bbadis.2019.165587)

    • Search Google Scholar
    • Export Citation
  • 40

    Harky A, Fan KS & Fan KH The genetics and biomechanics of thoracic aortic diseases. Vascular Biology 2019 1 R13R25. (https://doi.org/10.1530/VB-19-0027)

    • Search Google Scholar
    • Export Citation
  • 41

    Kerwin W, Pepin M, Mitsumori L, Yarnykh V, Schwarze U & Byers P MRI of great vessel morphology and function in Ehlers-Danlos syndrome type IV. International Journal of Cardiovascular Imaging 2008 24 519528. (https://doi.org/10.1007/s10554-007-9283-z)

    • Search Google Scholar
    • Export Citation
  • 42

    Conditions G Loeys-Dietz Syndrome: MedlinePlus Genetics 2020 [Internet] Medlineplus.gov [cited 23 December 2020]. (available at: https://medlineplus.gov/genetics/condition/loeys-dietz-syndrome/).

    • Search Google Scholar
    • Export Citation
  • 43

    Faggion Vinholo T, Zafar MA, Ziganshin BA & Elefteriades JA Nonsyndromic thoracic aortic aneurysms and dissections—is screening possible? Seminars in Thoracic & Cardiovascular Surgery 2019 31 628634. (https://doi.org/10.1053/j.semtcvs.2019.05.035)

    • Search Google Scholar
    • Export Citation
  • 44

    Ostberg NP, Zafar MA, Ziganshin BA & Elefteriades JA The genetics of thoracic aortic aneurysms and dissection: a clinical perspective. Biomolecules 2020 10. (https://doi.org/10.3390/biom10020182)

    • Search Google Scholar
    • Export Citation
  • 45

    Guo DC, Hostetler EM, Fan Y, Kulmacz RJ, Zhang DGenTAC Investigators, Nickerson DA, Leal SM, LeMaire SA & Regalado ES et al. Heritable thoracic aortic disease genes in sporadic aortic dissection. Journal of the American College of Cardiology 2017 70 27282730. (https://doi.org/10.1016/j.jacc.2017.09.1094)

    • Search Google Scholar
    • Export Citation
  • 46

    Lu H, Fagnant PM, Bookwalter CS, Joel P & Trybus KM Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin. Proceedings of the National Academy of Sciences of the United States of America 2015 112 E4168E4177. (https://doi.org/10.1073/pnas.1507587112)

    • Search Google Scholar
    • Export Citation
  • 47

    Yamashiro Y, Papke CL, Kim J, Ringuette LJ, Zhang QJ, Liu ZP, Mirzaei H, Wagenseil JE, Davis EC & Yanagisawa H Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. Science Signaling 2015 8 ra105. (https://doi.org/10.1126/scisignal.aab3141)

    • Search Google Scholar
    • Export Citation
  • 48

    Atkins SK, Cao K, Rajamannan NM & Sucosky P Bicuspid aortic valve hemodynamics induces abnormal medial remodeling in the convexity of porcine ascending aortas. Biomechanics & Modeling in Mechanobiology 2014 13 12091225. (https://doi.org/10.1007/s10237-014-0567-7)

    • Search Google Scholar
    • Export Citation
  • 49

    Bersi MR, Khosravi R, Wujciak AJ, Harrison DG & Humphrey JD Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension. Journal of the Royal Society, Interface 2017 14. (https://doi.org/10.1098/rsif.2017.0327)

    • Search Google Scholar
    • Export Citation
  • 50

    Mackie SL, Hensor EMA, Morgan AW & Pease CT Should i send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta-analysis. Annals of the Rheumatic Diseases 2014 73 143148. (https://doi.org/10.1136/annrheumdis-2012-202145)

    • Search Google Scholar
    • Export Citation
  • 51

    Ziganshin BA, Bailey AE, Coons C, Dykas D, Charilaou P, Tanriverdi LH, Liu L, Tranquilli M, Bale AE & Elefteriades JA Routine genetic testing for thoracic aortic aneurysm and dissection in a clinical setting. Annals of Thoracic Surgery 2015 100 1604161 1. (https://doi.org/10.1016/j.athoracsur.2015.04.106)

    • Search Google Scholar
    • Export Citation
  • 52

    Hannuksela M, Stattin EL, Johansson B & Carlberg B Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential carriers of the disease. Aorta 2015 3 18. (https://doi.org/10.12945/j.aorta.2015.14-052)

    • Search Google Scholar
    • Export Citation
  • 53

    Gu J, Hu J, Zhang HW, Xiao ZH, Fang Z, Qian H, Zhong MH, Guo YQ, Zhang EY & Shi YK et al. Time-dependent changes of plasma inflammatory biomarkers in type A aortic dissection patients without optimal medical management. Journal of Cardiothoracic Surgery 2015 10 3. (https://doi.org/10.1186/s13019-014-0199-0)

    • Search Google Scholar
    • Export Citation