Open access peer-reviewed chapter
Abstract
Being born with a bicuspid aortic valve (BAV) is a significant risk factor for developing an ascending aortic aneurysm (AscAA). Research has uncovered different mechanisms influencing AscAA development in BAV-patients compared to those with normal tricuspid aortic valves (TAV). BAV-associated AscAA may result from intrinsic hemodynamic or genetic alterations, possibly even embryonic origins. During embryonic development, neural crest cells and the second heart field contribute to the ascending aorta’s formation, with defective signaling potentially increasing susceptibility to aneurysm development. BAV can manifest with different phenotypes, impacting clinical outcomes. The degenerative AscAA in TAV-patients differs from BAV-associated AscAA, marked by fibrosis, smooth muscle cell loss, and inflammation. AscAA in TAV-patients rarely appears in those with aortic stenosis, suggesting a link between aortic valve disease and degenerative AscAA. This chapter aims to describe suggested molecular mechanisms driving aneurysm formation in BAV- and TAV-patients.
Keywords
- ascending aortic aneurysm
- bicuspid aortic valve
- embryology
- valvulogenesis
- vascular inflammation
- aortic stenosis
- aortic regurgitation
1. Introduction
Ascending aortic aneurysm (AscAA), defined as a dilatation of the ascending aorta 1.5 times the expected diameter [1], is a silent, potentially fatal disease with regrettably little known of its underlying pathomechanisms. The condition is most often discovered incidentally during radiological examinations, and no screening for the disease is performed. AscAA in general has a reported incidence of 5 per 100,000 patient-years [2]. The most significant risk factor for developing AscAA, with 80 times increased risk compared to the general population [3], is the common congenital heart malformation, the bicuspid aortic valve (BAV) [4, 5, 6]. The embryonic development of the aortic valve and ascending aorta are spatiotemporally associated, and implications of this, aortic flow disturbances and/or genetics have been proposed for the cooccurrence of BAV and AscAA [7, 8, 9]. Notably, the ascending aortic media is structurally well preserved in patients with concomitant aneurysm and BAV [10] (Figure 1A). Contrastingly, an aneurysm of the ascending aorta in patients with normal tricuspid aortic valves (TAV) is characterized by marked degenerative insults and immune cell infiltration [11] and almost exclusively occurs in association with aortic valve regurgitation, not aortic valve stenosis [12]. In this chapter, we will describe the potential effects of aortic valve cuspidity and aortic valve disease on ascending aortic aneurysm formation and development.
Figure 1.
(A) Movat pentachrome stainings of dilated aortas from patients with BAV (a, c) and TAV (b, d). In TAV-associated aneurysm, clear signs of degeneration, fibrosis, smooth muscle cell loss, and extracellular matrix component deposition can be seen. Magnification x20. Adapted from Freiholtz et al. [
2. A spatiotemporal embryonic association of the aorta and aortic valve
Valvulogenesis involves the initial formation of endocardial cushions in the atrioventricular canal and outflow tract via a process known as endocardial-to-mesenchymal transition. Specifically, delamination, endocardial cell migration, and remodeling events give rise to mesenchymal cells, subsequently forming the atrioventricular canal leaflets (mitral and tricuspid) and semilunar valves (aortic and pulmonary) [13]. However, lineage tracing studies in various animal models have demonstrated that the formation of semilunar valves is a more complex process involving other cell lineages, including cardiac neural crest cells as well as second heart field [14]. Interestingly, cardiac neural crest cells are crucial for arteriopulmonary septation and also give rise to vascular smooth muscle cells (VSMCs) of the ascending aorta and the aortic arch [15]. In the aortic root, the adluminal media is derived from neural crest cells, while the outer media/adventitia originates from second heart field [16, 17].
Evidently, there is a direct embryonic relationship of the adult ascending aorta and the aortic valve. During embryogenesis, various signaling pathways, such as Wnt/β-catenin, NOTCH, and transforming growth factor β (TGFβ), play a crucial role in regulating cell migration, proliferation, and extracellular matrix (ECM) deposition in the developing valves and ascending aortic wall [13, 18, 19, 20, 21, 22]. Defects in these signaling pathways may indeed lead to dysfunctional valvulogenesis and the formation of a BAV [15].
3. Embryonic origin of the bicuspid aortic valve: Impact on clinical manifestations of AscAA
BAV is the most common congenital malformation of the heart, with a prevalence of 1–2% in the general population [23]. It is characterized by the occurrence of two, as opposed to the normal three, aortic valvular cusps, and its morphotype may be classified by the number of raphe – a fusion of the lanulae valvarum of the left-coronary (L), the right-coronary (R) or the noncoronary cusp (N) [24]. A fusion of two cusps, confers a type-I BAV where the most common variant is fusion of the R and L cusps, followed by R–N and L–N. A type II BAV entails fusion of two raphe, and type 0 BAV represents a BAV with only two valvular sinus. Interestlingly, studies investigating the involvement of cardiac progenitor cells in the development of different BAV phenotypes have suggested that the type 1 BAV fusions R–L and R–N (i.e., the most common BAV phenotypes) have separate developmental aberrations. In particular, the R–L fusion was shown to be associated with abnormal behavior of neural crest cells [15], whereas an eNOS mutation has been proposed as a cause for the R–N fusion and a predisposition to aortic dilatation and dissection [25, 26]. The latter finding may suggest a role of second heart field in the development of type 1 R–N BAV as eNOS is expressed by endocardial cells, cardiomyocytes, and VSMCs, all of which are derived from the second heart field [27].
A possible consequence of different cardiac progenitor cells conferring different BAV phenotypes could be that specific regions of the ascending aorta are affected depending on the individual’s phenotype. Indeed, we and others have shown an association between BAV phenotype and different clinical manifestations [27, 28]. Furthermore, the R–L phenotype was associated with larger aortic root dimensions, which has been well-documented in echocardiography cohorts [29, 30, 31, 32]. Additionally, patients with type 0 BAV tended to present clinically at an earlier age than those with other phenotypes, and a similar trend was observed in men in this study [28]. Interestingly there are trends showing that R–L and type 0 phenotypes are associated with a higher prevalence of ascending aortic dilatation at any segment compared with the R–N phenotype, which relation to aortopathy has historically been conflictingly [28]. For instance, a large study on a surgical cohort reported a lack of ascending aortic root dilatation in combination with R–N phenotype [33].
4. Characteristics of BAV-associated ascending aortopathy
As described above, an association between impaired embryonic signaling between different cardiac progenitor cells and the formation of a BAV has been suggested, likely contributing to aortopathogenesis. The cardiac progenitor cells involved in valvulogenesis migrate and populate the ascending aortic media [18]. The literature has as such focused on the aortic media as causative of aortopathy. The adult ascending aortic media is laminarly structured with VSMCs sandwiched between load-bearing elastin and collagen [34]. Albeit BAV has been known as a risk factor for disease since 1844 [35], it was first during 1984, in necropsy studies by Larson et al., that structural differences between BAV-associated aortopathy and degenerative ascending aortic aneurysm were proposed in light of vastly different rates of acute aortic syndromes [36]. Histologically, one can observe very small differences in the ascending aorta of BAV patients with or without aneurysm, i.e., the elastin is intact, there is VSMC apoptosis, although notably without mucoid extracellular matrix accumulation (MEMA), and the aortic intima-media exhibits few signs of inflammation [10]. Still, the nondilated aorta of individuals with BAV displays a seemingly thinner intima [37].
In past years, researchers have focused on the aortic media in BAV-associated aortopathy with findings of differential VSMC phenotypes in BAV and TAV aortopathies [11, 38]. Not only have these cells been found to undergo apoptosis [39] without apparent MEMA [10], but BAV VSMCs also exhibit distinct morphology. In BAV patients, VSMCs are less differentiated, indicating a defect in the phenotypic switch process, leading to significantly lower expression of differentiated, contractile VSMC markers, such as smoothelin, calponin, and SM22alpha [40, 41]. Additionally, VSMC dissociated from aneurysmal tissue exhibit differences in proliferation and migration comparing BAV and TAV VSMC. Specifically, in an ORIS migration assay, TAV VSMCs showed a faster migration and a higher proliferation rate than BAV VSMCs [10]. Although these cells exhibit such characteristics and behavior in aneurysmal tissue, the less differentiated and immature VSMCs are observed in both nondilated and dilated BAV populations [40], leading the mind to wonder if this VSMC phenotype might itself not be driving aneurysm development.
Interestingly, we and others have observed a mesenchymal-like state of endothelial cells in the ascending aorta of BAV patients, even prior to aortic dilatation [7, 42, 43]. Moreover, the expression of the endothelial-specific marker CD31 is decreased in nondilated BAV aorta, indicating a less differentiated endothelial phenotype [10]. Also, there are signs of a compromised basal membrane, with decreased expression of laminin gamma 1 [10], the main monomer in laminin trimers of large artery basal membranes [44]. This, together with reports of alterations in endothelial junction protein expression in nondilated BAV, such as increased protein turnover of CDH5, decreased expression of CLDN5, and increased mRNA expression of
Thus, the endothelium, too, has a seemingly important role in the distinct aortic wall phenotype observed in BAV patients. This is further supported by numerous animal models with endothelial-specific mutations producing offspring with a higher prevalence of BAVs. Most notably, in regards to endothelial function, mice lacking eNOS result in 40% BAV progeny [25]. Mice with GATA5−/− (with 25% BAV progeny) indicate that dysfunctional endothelial phenotype, as they also display lower expression of endothelial-specific markers – CDH5, TIE2, and eNOS, is related to BAV [49]. However, a drawback of these studies is that the prevalence of, or propensity to develop, aortopathy was not investigated. Nonetheless, the endothelial-specificity of eNOS, and the fact that GATA5 is mostly restricted to the endocardium, disappearing at mid-gestation and is required for early differentiation of cardiac progenitors into endothelial/endocardial cells, suggests a connection between the BAV phenotype and disturbed endothelial function.
An observed consequence of impaired endothelial function related to BAV is increased permeability. Ascending aortas of nondilated and dilated BAV patients exhibit greater infiltration of albumin in the aortic intima-media compared to TAV patients, which in nondilated state have a normal functional endothelium [10, 46]. The infiltration of plasma proteins into the aortic wall of BAV patients and potential consequences to VSMC phenotype thereof has to our knowledge, not been investigated. It is, however, a promising line of research in search of circulating biomarkers influencing the cellular phenotype of ascending aortas in BAV patients. One might speculate that such a biomarker might guide practices of surveillance and indications of ascending aortic surgery.
5. Genetics and hemodynamics in BAV aortopathy
Analyses of the genetic contribution to BAV and its associate aortopathy in a large family-based study suggested that genetics and the presence of BAV independently influence ascending aortic diameter [50]. These investigations highlight the first and oldest hypothesis of BAV-associated AscAA development, namely the hemodynamic hypothesis [51]. Indeed, several studies have suggested a contribution of BAV-associated impaired flow to aneurysm development [52, 53]. A plethora of radiological tools, such as low-sensitive cardiac magnetic resonance imaging with full volumetric coverage of the ascending aorta, have allowed multiple flow-specific investigations on BAV aortopathy in the previous decade. As such, it is clear that hemodynamic alterations are intrinsic to BAV, even in the absence of severe valve disease, by virtue of its anatomy. Hemodynamic alterations in the presence of a BAV include flow jets, eccentric helical flow, and increased ascending aortic wall-shear stress. Observations of increased wall-shear stress and intramural stresses underpin the hypothesis that these hemodynamic alterations indeed participate in AscAA development and progression [54]. Not only are disturbances in ascending aortic flow pathognomic of BAV, but signs of flow-dependent cellular and histological changes have also been observed. Grewal et al. have published data suggesting a jet-associated phenotypic switch of the inner ascending aortic media by virtue of hemodynamic alterations [55]. Similarly, in support of a hemodynamic component in ascending aortopathy is a spatial differential expression of matrix proteins and smooth muscle cell depletion compared to a more circumferentially homogenous Marfan-or TAV-associated aorta [56, 57]. Furthermore, aortic endothelial cells isolated from BAV patients exhibit differential expression of flow-related
The second hypothesis of BAV development, i.e., the genetic hypothesis, is gaining more favor, and indeed genome-wide association studies are finding noncoding variants of genes like
Of note, exploration of genetic causes of nonfamilial BAV aortopathy cannot be disentangled from the concomitant hemodynamic alterations, and as such, both genetic and an altered hemodynamic are likely to contribute to disease development. This way, the current state of the literature warrants an integration of genetic and molecular factors being investigated in association with hemodynamic factors.
6. Degenerative ascending aortic aneurysm
While degenerative AscAA manifests with the same clinical manifestation as the BAV-associated AscAA, i.e., a dilated aorta, it is histomorphologically vastly different [67]. A comprehensive global gene expression analysis was conducted on ascending aortic intima-media obtained from both nondilated and dilated ascending aortas of 131 patients with BAV and TAV (i.e., degenerative AscAA), showing significant molecular disparities in the underlying pathophysiology between BAV and TAV- aortopathy [11]. The degenerative form of AscAA is marked by fibrotic, inflammatory, and degenerative changes [7, 68]. The histopathology of degenerative AscAA was first described by Erdheim in 1929 as idiopathic cystic medial necrosis [69]. Although this descriptor of the changes has been abandoned by contemporary science, the changes describe the loss of VSMCs with the subsequent accumulation of ECM components. Cystic medial necrosis is, by the current histopathological consensus on degenerative thoracic aortic disease [70], instead described as MEMA, whereby dead VSMCs deposit primarily collagens and proteoglycans to the site of injury [71]. Furthermore, one of the main load-bearing proteins, elastin [72], which, together with the VSMCs, make up the lamellar units of the vascular media, appear fragmented and thinned out with disease progression [70]. Furthermore, there are multiple reports of low-grade inflammation and infiltrated leukocytes into the aortic intima-media of degenerative AscAA [11].
Although the main histopathological characteristics of degenerative AscAA are described in the pathological consensus, structured histopathological studies reveal a degree of heterogeneity in AscAA tissue from patients undergoing ascending aortic repair. The degree of inflammatory activity and location of infiltrated leukocytes, i.e., subintimal or mid-media, varies without known associations to patient characteristics [11]. Noteworthy is also the reported experience of surgeons treating aortic diseases, where degenerative AscAA differ significantly from descending aortic aneurysm or abdominal aortic aneurysms (AAA), in particular with respect to the absence of mural thrombi or macroscopic signs of atherosclerosis [73]. Taken together, this indicates, in our minds, that the degenerative changes described in the pathological consensus apply to most AscAA patients despite some reports of heterogeneity as pronounced inflammation or microscopic atherosclerotic lesions.
AscAA in patients with tricuspid aortic valves can manifest as part of monogenic syndromes, where inherited genetic mutations play a significant role in the development of aortopathy. Mutations in genes encoding ECM proteins, such as FBN1 in Marfan syndrome, COL3A1 in vascular Ehlers–Danlos syndrome, and TGFBR1 and TGFBR2 in Loeys–Dietz syndrome, disrupt the structural integrity of the aortic wall [74]. These mutations lead to abnormal ECM synthesis, impaired collagen and elastin assembly, and risk of ascending aortic dilatation.
In the absence of monogenic diseases, molecular drivers of degenerative AscAA development may be matrix metalloproteinsases (MMP), TGFβ signaling pathway disruptions, and inflammation [11, 75]. MMPs are a family of enzymes involved in the breakdown of ECM components. Excessive MMP activity has been observed in AscAA, particularly MMP-2 [76], −3 [77], −9 [78], −14, and − 19 [79]. Increased MMP expression and degraded ECM structures, such as elastin, induce VSMC death, weakening the aortic wall and promoting aneurysm formation [80]. Dysregulated TGFβ signaling is central in AscAA in monogenic conditions like Marfan syndrome and Loeys–Dietz syndrome [81, 82] but may too contribute to disease progression in polygenic contexts. The disruption of TGFβ signaling results in increased production of TGFβ ligands, which, paradoxically, can lead to defective TGFβ signaling and impaired ECM maintenance and turnover [83]. Altered TGF-β signaling disrupts the balance between ECM synthesis and degradation, consequently leading to aneurysm development. Inflammatory processes also play a role in degenerative AscAA pathogenesis. Macrophages and T lymphocytes infiltrate the aortic wall, releasing pro-inflammatory cytokines and chemokines with reports of upregulated inflammatory genes [84]. This immune system activation contributes to chronic inflammation, subsequent oxidative stress, and ECM remodeling, thereby exacerbating degenerative characteristics and aneurysm growth [85, 86, 87, 88].
The clear difference between degenerative and BAV-associated AscAA strengthens the idea that these diseases are indeed separate. Instead, degenerative AscAA appears more similar to AAA at a molecular level, although genetic analyses have demonstrated a limited overlap [74, 89].
Atherosclerotic processes are often implicated in AAA, with accumulation of lipids, immune cells, and ECM components within the abdominal aortic wall [90]. Lipid deposition and macrophage infiltration contributes to the release of pro-inflammatory cytokines and the production of reactive oxygen species, resulting in chronic inflammation, endothelial dysfunction, and vascular degeneration [91, 92]. Oxidative stress further promotes inflammation, ECM degradation, and apoptosis of vascular cells, exacerbating AAA progression [93]. Moreover, proteolytic enzymes, such as MMPs (in particular MMP-1, −2, −3, −9, −12, and − 13) and elastases, are secreted by immune and vascular SMCs leading to increased degradation of ECM components and weakening the abdominal aortic wall [80, 94]. Of note, in the context of differential mechanisms driving aneurysm development, the abdominal aorta is subject to different hemodynamic forces than the ascending aorta, including flow disturbances, pulsatile flow, and increased wall-shear stress. These hemodynamic forces induce endothelial dysfunction, inflammation, and arterial wall remodeling, contributing to AAA formation [95]. Of note, intracranial aneurysms (IAs) are also influenced by hemodynamic forces, specifically in the context of formation and rupture [96]. Regions of disturbed flow, such as bifurcations and curvatures, are particularly vulnerable [96]. Also, similarly to AscAA and AAA, proteolytic enzymes (e.g., MMP-2 and -9) are involved in the pathogenesis of IA [97].
Genetic predisposition also plays a significant role in IA development. Mutations in genes encoding components of the ECM, such as collagen type IV alpha-1 and alpha-2, have been identified in familial cases of IA [98, 99]. These mutations hamper the structural integrity of the intracranial arterial wall, causing a propensity to IA formation. Inflammation and immune responses also contribute to IA pathogenesis. Inflammatory cells infiltrate the arterial wall, releasing cytokines and promoting oxidative stress [100, 101, 102]. This leads to ECM degradation, smooth muscle cell apoptosis, and arterial wall remodeling, ultimately contributing to aneurysm formation and growth (Figure 2).
Figure 2.
Matrix metalloproteinases associated with degenerative aneurysmal disease.
It is important to note that while there are similarities in the molecular drivers between AscAA, IA, and AAA, there are also distinct differences. AscAA is often associated with monogenic connective tissue disorders or proteolytic enzyme degenerative effects, whereas IAs are more often influenced by polygenic genetic factors, hemodynamic forces, and inflammation [103]. AAA is influenced by atherosclerotic processes, proteolytic enzyme activity, oxidative stress, hemodynamic forces, inflammation, and ECM remodeling [74, 98]. It is important to note that while these molecular drivers are often associated with AscAA, IA, and AAA, there can be considerable heterogeneity in the underlying mechanisms between individual patients. Moreover, there may be overlapping molecular pathways and interactions, requiring further studies. Understanding the molecular drivers of aneurysmal disease is crucial for developing targeted therapies and interventions to prevent its progression and improve patient outcomes.
7. Implications of aortic valve disease on degenerative ascending aortic aneurysm
There are signs that degenerative AscAA is also associated with aortic valve disease when examining the surgical ASAP-cohort (described in detail elsewhere [12]); BAV-associated aortopathy has an equal prevalence of aortic stenosis (AS) and aortic regurgitation (AI). Contrastingly TAV-associated (degenerative) AscAA often associates with AI but very seldomly AS. This may imply that AS has protective effects on AscAA development, or the inverse, that AscAA patients are protected from AS.
The association of AI with degenerative AscAA may in part represent secondary causes of AI, i.e., disease of surrounding structures [104]. However, AI, combined with degenerative AscAA, was also prevalent in the absence of aortic root dilatation, as seen in the ASAP cohort, pointing toward a primary cause of AI to AscAA formation. Notably, AI is a well-known prognostic factor in clinical outcomes of patients undergoing ascending aortic repair [105]. A worse surgical outcome for AscAA/AI repair is reported in both BAV and TAV individuals [106].
Interestingly, further strengthening the association of AI to AscAA formation is the fact that degenerative changes are noted in ascending aortas of patients with normal aortic diamters and AI. Specifically, elastin fragmentation, thinning and MEMA (indicative of VSMC death) have been observed in patients with AI but not AS [105, 107]. One apparent line of investigation not yet explored is whether this association can be observed in individuals with BAV without dilatation but with respective aortic valve disease [37]. Neither have implications of AI-associated ascending aortic degeneration been investigated as a possible player in AscAA formation.
8. Summary
In summary, the impact of aortic valve cuspidity on ascending aortic aneurysm is well-established. Specifically, BAV aortopathy has been associated with endothelial instability and endothelial-to-mesenchymal transition, possibly of embryonic origin. Moreover, different BAV fusion types may impose different mechanisms of aortopathy, with different aortic segments being affected. TAV-associated degenerative aneurysms, on the other hand, are molecularly more similar to AAA with clear medial degeneration and inflammation. Also, aortic valve disease may play a role in degenerative aneurysm formation, with aortic dilatation occurring almost exclusively in combination with aortic regurgitation. This is further supported by histopathological evidence.
As the aortic valve and ascending aorta are not only anatomically proximate but also embryonically associated and physiologically interacting, the impact of aortic valve cuspidity and disease on ascending aortopathy is warranted further research specifically to explore more patient-specific molecular mechanisms. An elucidation of the molecular underpinnings of AscAA development in different conditions of the aortic valve will help guide novel diagnosis and treatment strategies.
References
- 1.
Isselbacher EM, Preventza O, Black JH, Augoustides JG, Beck AW, Bolen MA, et al. 2022 ACC/AHA guideline for the diagnosis and Management of Aortic Disease: A report of the American Heart Association/American College of Cardiology Joint Committee on clinical practice guidelines. Circulation. 2022; 146 (24):E334-E482 - 2.
Gouveia e Melo R, Silva Duarte G, Lopes A, Alves M, Caldeira D, e Fernandes RF, et al. Incidence and prevalence of thoracic aortic aneurysms: A systematic review and meta-analysis of population-based studies. Seminars in Thoracic and Cardiovascular Surgery. 2022; 34 (1):1-16 - 3.
Michelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri RM, et al. Incidence of aortic complications in patients with bicuspid aortic valves. Journal of the American Medical Association. 2011; 306 (10):1104-1112 - 4.
Sillesen AS, Vøgg O, Pihl C, Raja AA, Sundberg K, Vedel C, et al. Prevalence of bicuspid aortic valve and associated Aortopathy in Newborns in Copenhagen, Denmark. JAMA - Journal of the American Medical Association. 2021; 325 (6):561-567 - 5.
Masri A, Kalahasti V, Alkharabsheh S, Svensson LG, Sabik JF, Roselli EE, et al. Characteristics and long-term outcomes of contemporary patients with bicuspid aortic valves. Journal of Thoracic and Cardiovascular Surgery. 2016; 151 (6):1650-1659 - 6.
Masri A, Svensson LG, Griffin BP, Desai MY. Contemporary natural history of bicuspid aortic valve disease: A systematic review. Vol. 103. Heart. 2017; 103 (17):1323-1330 - 7.
Grewal N, Gittenberger-De Groot AC, von der Thusen J, Wisse LJ, Bartelings MM, Deruiter MC, et al. The development of the ascending aortic wall in tricuspid and bicuspid aortic valve: A process from maturation to degeneration. Journal of Clinical Medicine. 2020; 9 (4):908 - 8.
Stock S, Mohamed SA, Sievers HH. Bicuspid aortic valve related aortopathy. General Thoracic and Cardiovascular Surgery. 2019; 67 (1):93-101 - 9.
Abdulkareem N, Smelt J, Jahangiri M. Bicuspid aortic valve aortopathy: Genetics, pathophysiology and medical therapy. Interactive Cardiovascular and Thoracic Surgery. 2013; 17 (3):554-559 - 10.
Freiholtz D, Bergman O, Lång K, Poujade FA, Paloschi V, Granath C, et al. Bicuspid aortic valve aortopathy is characterized by embryonic epithelial to mesenchymal transition and endothelial instability. Journal of Molecular Medicine. 2023; 1 :1-11 - 11.
Folkersen L, Wågsäter D, Paloschi V, Jackson V, Petrini J, Kurtovic S, et al. Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: The ASAP study. Molecular Medicine. 2011; 17 (11-12):1365-1373 - 12.
Jackson V, Petrini J, Caidahl K, Eriksson MJ, Liska J, Eriksson P, et al. Bicuspid aortic valve leaflet morphology in relation to aortic root morphology: A study of 300 patients undergoing open-heart surgery. European Journal of Cardio-thoracic Surgery. 2011; 40 (3):e118-e124 - 13.
Hinton RB, Lincoln J, Deutsch GH, Osinska H, Manning PB, Benson DW, et al. Extracellular matrix remodeling and organization in developing and diseased aortic valves. Circulation Research. 2006; 98 (11):1431-1438 - 14.
Stefanovic S, Etchevers HC, Zaffran S. Outflow tract formation—Embryonic origins of Conotruncal congenital heart disease. Journal of Cardiovascular Development and Disease. 2021; 8 (4):42 - 15.
Grewal N, Lindeman JH, Klautz A, Driessen A, Klautz RJM, Poelmann RE. Normal and abnormal development of the aortic valve and ascending aortic wall: A comprehensive overview of the embryology and pathology of the bicuspid aortic valve. Annals of Cardiothoracic Surgery. 2022; 11 (4):380-388 - 16.
Phillips HM, Mahendran P, Singh E, Anderson RH, Chaudhry B, Henderson DJ. Neural crest cells are required for correct positioning of the developing outflow cushions and pattern the arterial valve leaflets. Cardiovascular Research. 2013; 99 (3):452-460 - 17.
Soto-Navarrete MT, López-Unzu MÁ, Durán AC, Fernández B. Embryonic development of bicuspid aortic valves. Progress in Cardiovascular Diseases. 2020; 63 (4):407-418 - 18.
Armstrong EJ, Bischoff J. Heart Valve Development. Circulation Research. 2004; 95 (5):459-470 - 19.
De la Pompa JL, Epstein JA. Coordinating tissue interactions: Notch Signaling in cardiac development and disease. Developmental Cell. 2012; 22 (2):244-254 - 20.
Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139 (5):871-890 - 21.
Wang Y, Fang Y, Lu P, Wu B, Zhou B. NOTCH Signaling in aortic valve development and calcific aortic valve disease. Frontiers in Cardiovascular Medicine . 2021;8 :682298 - 22.
High FA, Zhang M, Proweller A, Tu LL, Parmacek MS, Pear WS, et al. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. Journal of Clinical Investigation. 2007; 117 (2):353-363 - 23.
Tutar E, Ekici F, Atalay S, Nacar N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. American Heart Journal. 2005; 150 (3):513-515 - 24.
Sievers HH, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. Journal of Thoracic and Cardiovascular Surgery. 2007; 133 (5):1226-1233 - 25.
Peterson JC, Wisse LJ, Wirokromo V, van Herwaarden T, Smits AM, Gittenberger-De Groot AC, et al. Disturbed nitric oxide signalling gives rise to congenital bicuspid aortic valve and aortopathy. DMM Disease Models and Mechanisms. 2020; 13 (9):dmm044990 - 26.
Aicher D, Urbich C, Zeiher A, Dimmeler S, Schäfers HJ. Endothelial nitric oxide synthase in bicuspid aortic valve disease. Annals of Thoracic Surgery. 2007; 83 (4):1290-1294 - 27.
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, and Vascular Biology. 2017; 37 (9):1722-1726 - 28.
Granath C, Mohamed SA, Olsson C, Grattan M, Mertens L, Franco-Cereceda A, et al. Valve disease and aortopathy associations of bicuspid aortic valve phenotypes differ between men and women. Open Heart. 2021; 8 (2):e001857 - 29.
Habchi KM, Ashikhmina E, Vieira VM, Shahram JT, Isselbacher EM, Sundt TM, et al. Association between bicuspid aortic valve morphotype and regional dilatation of the aortic root and trunk. The International Journal of Cardiovascular Imaging. 2017; 33 (3):341-349 - 30.
Evangelista A, Gallego P, Calvo-Iglesias F, Bermejo J, Robledo-Carmona J, Sánchez V, et al. Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease. Heart. 2018; 104 (7):566-573 - 31.
Della CA, Bancone C, Dialetto G, Covino EFE, Manduca S, Montibello VMV, et al. The ascending aorta with bicuspid aortic valve: A phenotypic classification with potential prognostic significance. European Journal of Cardio-Thoracic Surgery. 2014; 46 (2):240-247 - 32.
Roman MJ, Pugh NL, Devereux RB, Eagle KA, Holmes K, LeMaire SA, et al. Aortic dilatation associated with bicuspid aortic valve: Relation to sex, Hemodynamics, and valve morphology (the National Heart Lung and blood institute-sponsored National Registry of genetically triggered thoracic aortic aneurysms and cardiovascular conditions). The American Journal of Cardiology. 2017; 120 (7):1171-1175 - 33.
Jackson V, Olsson C, Eriksson P, Franco-Cereceda A. Aortic dimensions in patients with bicuspid and tricuspid aortic valves. Journal of Thoracic and Cardiovascular Surgery. 2013; 146 (3):605-610 - 34.
Kusner JJ, Brown JY, Gleason TG, Edelman ER. The natural history of bicuspid aortic valve disease. Structure Heart. 2022; 7 (2):100119 - 35.
Braverman AC, Güven H, Beardslee MA, Makan M, Kates AM, Moon MR. The bicuspid aortic valve 470 Curr Probl Cardiol, September 2005. Current Problems in Cardiology. 2005; 30 :470-522 - 36.
Larson EW, Edwards WD. Risk factors for aortic dissection: A necropsy study of 161 cases. The American Journal of Cardiology. 1984; 53 (6):849-855 - 37.
Grewal N, Girdauskas E, Idhrees M, Velayudhan B, Klautz R, Driessen A, et al. Structural abnormalities in the non-dilated ascending aortic wall of bicuspid aortic valve patients. Cardiovascular Pathology. 2023; 62 :107478 - 38.
Maleki S, Björck HM, Paloschi V, Kjellqvist S, Folkersen L, Jackson V, et al. Aneurysm development in patients with bicuspid aortic valve (BAV): Possible connection to repair deficiency? Aorta (Stamford). 2013; 1 (1):13-22 - 39.
Balint B, Yin H, Nong Z, Arpino JM, O’Neil C, Rogers SR, et al. Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease. eBioMedicine. 2019; 43 :54-66 - 40.
Ignatieva E, Kostina D, Irtyuga O, Uspensky V, Golovkin A, Gavriliuk N, et al. Mechanisms of smooth muscle cell differentiation are distinctly altered in thoracic aortic aneurysms associated with bicuspid or tricuspid aortic valves. Frontiers in Physiology. 2017; 8 :536 - 41.
Ailawadi G, Moehle CW, Pei H, Walton SP, Yang Z, Kron IL, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. Journal of Thoracic and Cardiovascular Surgery. 2009; 138 (6):1392-1399 - 42.
Maleki S, Poujade FA, Bergman O, Gådin JR, Simon N, Lång K, et al. Endothelial/epithelial mesenchymal transition in ascending aortas of patients with bicuspid aortic valve. Frontiers in Cardiovascular Medicine. 2019; 6 :182 - 43.
Björck HM, Du L, Pulignani S, Paloschi V, Lundströmer K, Kostina AS, et al. Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve. Scientific Reports. 2018; 8 (1):2777 - 44.
Di Russo J, Hannocks MJ, Luik AL, Song J, Zhang X, Yousif L, et al. Vascular laminins in physiology and pathology. Matrix Biology. 2017; 57-58 :140-148 - 45.
Maleki S, Kjellqvist S, Paloschi V, Magné J, Branca RMM, Du L, et al. Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves. Scientific Reports. 2016; 6 (June):1-16 - 46.
Gould RA, Aziz H, Woods CE, Seman-Senderos MA, Sparks E, Preuss C, et al. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Vol. 51. Nature Genetics. 2019; 51 (1):42-50 - 47.
Park KW, Morrison CM, Sorensen LK, Jones CA, Rao Y, Bin CC, et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Developmental Biology. 2003; 261 (1):251-267 - 48.
Okada Y, Yano K, Jin E, Funahashi N, Kitayama M, Doi T, et al. A three-kilobase fragment of the human Robo4 promoter directs cell type-specific expression in endothelium. Circulation Research. 2007; 100 (12):1712-1722 - 49.
Laforest B, Andelfinger G, Nemer M. Loss of Gata5 in mice leads to bicuspid aortic valve. Journal of Clinical Investigation. 2011; 121 (7):2876-2887 - 50.
Martin LJ, Hinton RB, Zhang X, Cripe LH, Benson DW. Aorta measurements are heritable and influenced by bicuspid aortic valve. Frontiers in Genetics. 2011; 2 :61. DOI: 10.3389 - 51.
Girdauskas E, Borger MA, Secknus MA, Girdauskas G, Kuntze T. Is aortopathy in bicuspid aortic valve disease a congenital defect or a result of abnormal hemodynamics? A critical reappraisal of a one-sided argument. European Journal of Cardio-Thoracic Surgery. 2011; 39 (6):809-814 - 52.
den Reijer PM, Sallee D 3rd, van der Velden P, Zaaijer ER, Parks WJ, Ramamurthy S, et al. Hemodynamic predictors of aortic dilatation in bicuspid aortic valve by velocity-encoded cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance: official journal of the Society for Cardiovascular Magnetic Resonance. 2010; 12 (1):4. doi: 10.1186/1532-429X-12-4 - 53.
Hope MD, Hope TA, Meadows AK, Ordovas KG, Urbania TH, Alley MT, et al. Bicuspid aortic valve: Four-dimensional MR evaluation of ascending aortic systolic flow patterns. Radiology. 2010; 255 (1):53-61 - 54.
Pasta S, Gentile G, Raffa GM, Bellavia D, Chiarello G, Liotta R, et al. In Silico shear and intramural stresses are linked to aortic valve morphology in dilated ascending aorta. European Journal of Vascular and Endovascular Surgery. 2017; 54 (2):254-263 - 55.
Grewal N, Girdauskas E, DeRuiter M, Goumans MJ, Lindeman JH, Disha K, et al. The role of hemodynamics in bicuspid aortopathy: A histopathologic study. Cardiovascular Pathology. 2019; 41 :29-37 - 56.
Cotrufo M, Della Corte A, De Santo LS, Quarto C, De Feo M, Romano G, et al. Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: Preliminary results. The Journal of Thoracic and Cardiovascular Surgery. 2005; 130 (2):504-511 - 57.
Della Corte A, Quarto C, Bancone C, Castaldo C, Di Meglio F, Nurzynska D, et al. Spatiotemporal patterns of smooth muscle cell changes in ascending aortic dilatation with bicuspid and tricuspid aortic valve stenosis: Focus on cell-matrix signaling. Journal of Thoracic and Cardiovascular Surgery. 2008; 135 (1):8-18 - 58.
Maleki S, Björck HM, Folkersen L, Nilsson R, Renner J, Caidahl K, et al. Identification of a novel flow-mediated gene expression signature in patients with bicuspid aortic valve. Journal of Molecular Medicine. 2013; 91 (1):129-139 - 59.
Gauer S, Balint B, Kollmann C, Federspiel JM, Henn D, Bandner-Risch D, et al. Dysregulation of endothelial nitric oxide synthase does not depend on hemodynamic alterations in bicuspid aortic valve aortopathy. Journal of the American Heart Association. 2020; 9 (18):e016471 - 60.
Regeer MV, Versteegh MIM, Klautz RJM, Schalij MJ, Bax JJ, Marsan NA, et al. Effect of aortic valve replacement on aortic root dilatation rate in patients with bicuspid and tricuspid aortic valves. Annals of Thoracic Surgery. 2016; 102 (6):1981-1987 - 61.
Yoshioka Y, Yajima S, Sakaniwa R, Tadokoro N, Kainuma S, Kawamoto N, et al. Does the residual aorta dilate after replacement of the bicuspid aortic valve and ascending aorta? Journal of Thoracic Disease. 2023; 15 (3):994-1008 - 62.
Yang B, Zhou W, Jiao J, Nielsen JB, Mathis MR, Heydarpour M, et al. Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve. Nature Communications. 2017; 8 :15481 - 63.
Abbasi S, Mohsen-Pour N, Naderi N, Rahimi S, Maleki M, Kalayinia S. In silico analysis of GATA4 variants demonstrates main contribution to congenital heart disease. Journal of Cardiovascular and Thoracic Research. 2021; 13 (4):336-354 - 64.
Behiry EG, Al-Azzouny MA, Sabry D, Behairy OG, Salem NE. Association of NKX2-5, GATA4, and TBX5 polymorphisms with congenital heart disease in Egyptian children. Molecular Genetics & Genomic Medicine. 2019; 7 (5):e612 - 65.
Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003; 424 (6947):443-447. DOI: 10.1038/nature01827 - 66.
Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, et al. Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor. Frontiers in Physiology. 2017; 8 :400 - 67.
Heng E, Stone JR, Kim JB, Lee H, MacGillivray TE, Sundt TM. Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves. Annals of Thoracic Surgery. 2015; 100 (6):2095-2101 - 68.
Federspiel JM, Schnabel PA, Tschernig T, Balint B, Schwab T, Laschke MW, et al. Aortic aneurysms with tricuspid aortic valve have more degeneration than unicuspid aortic valve aneurysms. European Journal of Cardio-thoracic Surgery. 2021; 60 (2):333-340 - 69.
Erdheim J. Medionecrosis aortae idiopathica. Virchows Archiv für Pathologische Anatomie und Physiologie und für Klinische Medizin. 1929; 273 (2):454-479 - 70.
Halushka MK, Angelini A, Bartoloni G, Basso C, Batoroeva L, Bruneval P, et al. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the association for European cardio-vascular pathology: II. Noninflammatory Degenerative Diseases-Nomenclature and Diagnostic Criteria Cardiovascular Pathology. 2016; 25 (3):247-257 - 71.
Leone O, Pacini D, Foà A, Corsini A, Agostini V, Corti B, et al. Redefining the histopathologic profile of acute aortic syndromes: Clinical and prognostic implications. The Journal of Thoracic and Cardiovascular Surgery. 2018; 156 (5):1776-1785 - 72.
Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. Journal of Cardiovascular Translational Research. 2012; 5 (3):264-273 - 73.
Weininger G, Ostberg N, Shang M, Zafar M, Ziganshin BA, Liu S, et al. Lipid profiles help to explain protection from systemic atherosclerosis in patients with ascending aortic aneurysm. Journal of Thoracic and Cardiovascular Surgery. 2022; 163 (2):e129-e132 - 74.
Pinard A, Jones GT, Milewicz DM. Genetics of thoracic and abdominal aortic diseases. Circulation Research. 2019; 124 (4):588-606 - 75.
Ikonomidis JS, Ruddy JM, Benton SM, Arroyo J, Brinsa TA, Stroud RE, et al. Aortic dilatation with bicuspid aortic valves: Cusp fusion correlates to matrix metalloproteinases and inhibitors. Annals of Thoracic Surgery. 2012; 93 (2):457-463 - 76.
Rabkin SW. Differential expression of MMP-2, MMP-9 and TIMP proteins in thoracic aortic aneurysm - comparison with and without bicuspid aortic valve: A meta-analysis. VASA. 2014; 43 (6):433-442 - 77.
Matusiewicz M et al. Upregulated sulfatase and downregulated MMP-3 in thoracic aortic aneurysm. Advances in Clinical and Experimental Medicine. 2020; 29 (5):565-572 - 78.
Lemaire SA, Wang X, Wilks JA, Carter SA, Wen S, Won T, et al. Matrix metalloproteinases in ascending aortic aneurysms: Bicuspid versus trileaflet aortic valves1. Journal of Surgical Research. 2005; 123 (1):40-48 - 79.
Jackson V, Olsson T, Kurtovic S, Folkersen L, Paloschi V, Wågsäter D, et al. Matrix metalloproteinase 14 and 19 expression is associated with thoracic aortic aneurysms. The Journal of Thoracic and Cardiovascular Surgery. 2012; 144 (2):459-466 - 80.
Rabkin SW. The role matrix Metalloproteinases in the production of aortic aneurysm. Progress in Molecular Biology and Translational Science. 2017; 147 :239-265 - 81.
Velchev JD, Van Laer L, Luyckx I, Dietz H, Loeys B. Loeys-Dietz Syndrome. Advances in Experimental Medicine and Biology. 2021; 1348 :251-264 - 82.
Zeigler SM, Sloan B, Jones JA. Pathophysiology and pathogenesis of Marfan syndrome. Advances in Experimental Medicine and Biology. 2021; 1348 :185-206 - 83.
Isselbacher EM, Cardenas CLL, Lindsay ME. Hereditary influence in thoracic aortic aneurysm and dissection. Circulation. 2016; 133 (24):2516-2528 - 84.
Li Y, Ren P, Dawson A, Vasquez HG, Ageedi W, Zhang C, et al. Single-cell transcriptome analysis reveals dynamic cell populations and differential gene expression patterns in control and aneurysmal human aortic tissue. Circulation. 2020; 142 (14):1374-1388 - 85.
Kuzmik GA, Sang AX, Elefteriades JA. Natural history of thoracic aortic aneurysms. Journal of Vascular Surgery. 2012; 56 (2):565-571 - 86.
Pannu H, Tran-Fadulu V, Milewicz DM. Genetic basis of thoracic aortic aneurysms and aortic dissections. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 2005; 139C (1):10-16 - 87.
Saeyeldin A, Velasquez C, Mahmood S, Brownstein A, Zafar M, Ziganshin B, et al. Thoracic aortic aneurysm: Unlocking the “silent killer” secrets. General Thoracic and Cardiovascular Surgery. 2019; 67 (1):1-11 - 88.
He R, Guo DC, Sun W, Papke CL, Duraisamy S, Estrera AL, et al. Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms. Journal of Thoracic and Cardiovascular Surgery. 2008; 136 (4):922-929 - 89.
Gyftopoulos A, Ziganshin BA, Elefteriades JA, Ochoa Chaar CI. Comparison of genes associated with thoracic and abdominal aortic aneurysms. Aorta (Stamford, Conn.). 2023; 11 (3):125-134. DOI: 10.1055/s-0043-57266 - 90.
Sakalihasan N, Limet R, Defawe OD. Abdominal aortic aneurysm. Vol. 365. Lancet. 2005; 365 (9470):1577-1589 - 91.
Golledge J. Abdominal aortic aneurysm: Update on pathogenesis and medical treatments. Nature Reviews. Cardiology. 2019; 16 (4):225-242 - 92.
Deroo E, Stranz A, Yang H, Hsieh M, Se C, Zhou T. Endothelial dysfunction in the pathogenesis of abdominal aortic aneurysm. Biomolecules. 2022; 12 (4):509 - 93.
Wiernicki I, Parafiniuk M, Kolasa-Wolosiuk A, Gutowska I, Kazimierczak A, Clark J, et al. Relationship between aortic wall oxidative stress/proteolytic enzyme expression and intraluminal thrombus thickness indicates a novel pathomechanism in the progression of human abdominal aortic aneurysm. The FASEB Journal. 2019; 33 (1):885-895 - 94.
Jacob MP. Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomedicine and Pharmacotherapy. 2003; 57 (5-6):195-202 - 95.
Gao JP, Guo W. Mechanisms of abdominal aortic aneurysm progression: A review. Vascular Medicine. 2022; 27 (1):88-96 - 96.
Brown RD, Broderick JP. Unruptured intracranial aneurysms: Epidemiology, natural history, management options, and familial screening. Lancet Neurology. 2014; 13 (4):393-404 - 97.
Laurent D, Small C, Lucke-Wold B, Dodd WS, Chalouhi N, Hu YC, et al. Understanding the genetics of intracranial aneurysms: A primer. Clinical Neurology and Neurosurgery. 2022; 212 :107060. DOI: 10.1016/j.clineuro.2021.107060 - 98.
Bakker MK, Ruigrok YM. Genetics of intracranial aneurysms. Stroke. 2021; 52 (9):3004-3012 - 99.
Ruigrok YM, Rinkel GJE, Wijmenga C. Genetics of intracranial aneurysms. Lancet Neurology. 2005; 4 (3):179-189 - 100.
Zhang Z, Fang Y, Lenahan C, Chen S. The role of immune inflammation in aneurysmal subarachnoid hemorrhage. Experimental Neurology. 2021; 336 :113535. DOI: 10.1016/j.expneurol.2020.113535 - 101.
Jin J, Duan J, Du L, Xing W, Peng X, Zhao Q. Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies. Frontiers in Immunology. 2022; 13 :1027756 - 102.
Okada T, Suzuki H. Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage. Neural Regeneration Research. 2017; 12 (2):193-196 - 103.
Samuel N, Radovanovic I. Genetic basis of intracranial aneurysm formation and rupture: Clinical implications in the postgenomic era. Neurosurgical Focus. 2019; 47 (1):E10 - 104.
Akinseye OA, Pathak A, Ibebuogu UN. Aortic valve regurgitation: A comprehensive review. Current Problems in Cardiology. 2018; 43 (8):315-334 - 105.
Benedik J, Pilarzcyk K, Wendt D, Price V, Tsagakis K, Perrey M, et al. Is there any difference in aortic wall quality between patients with aortic stenosis and those with regurgitation? European Journal of Cardio-Thoracic Surgery: official Journal of the European Association for Cardio-thoracic Surgery. 2013; 44 (4):754-759. DOI: 10.1093/ejcts/ezt123 - 106.
Balint B, Federspiel JM, Schwab T, Ehrlich T, Ramsthaler F, Schäfers HJ. Aortic regurgitation is associated with ascending aortic Remodeling in the nondilated aorta. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021; 41 (3):1179-1190 - 107.
Sequeira Gross TM, Lindner D, Ojeda FM, Neumann J, Grewal N, Kuntze T, et al. Comparison of microstructural alterations in the proximal aorta between aortic stenosis and regurgitation. Journal of Thoracic and Cardiovascular Surgery. 2021; 162 (6):1684-1695