Patients with Bicuspid Aortopathy and Aortic Dilatation: History
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Bicuspid aortic valve (BAV) is the most frequent congenital cardiac disease. Alteration of ascending aorta diameter is a consequence of shear stress alterations due to haemodynamic abnormalities developed from inadequate valve cusp coaptation.

  • bicuspid aortic valve
  • aortopathy
  • classification

1. Introduction

Bicuspid aortic valve (BAV) is the most frequent congenital cardiac pathology; has a prevalence of 1–2% [1], a high incidence of adverse outcomes, especially aortic stenosis (AS) and aortic regurgitation (MR) [2]; and is at least three times more common in males than females [3].
Bicuspid aortopathy, reported in 50% of BAV patients, consists of the aorta enlargement starting from the aortic root and involving the aortic arch and depends on blood flux turbulences characterized by power vectors directed against the aortic toot and the convexity of the vessel [4,5,6,7]. Recently, micro-RNA (miRNA) has been studied regarding post-transcriptional regulation of genes in aortopathy manifestation. [8,9].

2. Genetics and Molecular Biology

Estimating mutation genes and their inheritance patterns is challenging [7] because locus 9q34.3 alteration causes mutations in regulators NOTCH1 with secondary pathological aortic valve development [10,11]; gene damages on 18q, 5q, and 13q induces BAV [12]; and finally, damages to the smooth muscle alfa actine (ACTA 2) gene produce BAV and aortic aneurysms [13].
There is a tight linkage between BAV expression and other congenital pathologies such as the coarctation of the aorta. Concerning BAV phenotype, Shone’s syndrome with a left-sided lesion that can cause inflow and outflow obstruction, Turner’s syndrome with aortic coarctation, and William’s syndrome involving supravalvular stenosis may be observed. Moreover, ventricular septal defect, atrial septal defect, patent ductus arteriosus, and coronary vessels, which may mainly involve single coronary and reversal coronary dominance, have been reported [14,15,16].
Micro-RNAs (MiRNAs) need to be considered in biochemical and molecular changes in BAV and aorthopathy (Table 2). MiRNAs are small, single-stranded, noncoding RNA molecules that determine the post-transcriptional regulation of gene expression. The effects of miRNAs are the result of base pairing with complementary sequences within mRNA molecules that are silenced by cleavage of the mRNA strand, destabilization of the mRNA by shortening its tail, and less efficient translation into proteins by ribosomes [17]. MiRNA expression profiling studies show that the expression levels of certain miRNAs change in diseased human hearts, suggesting their involvement in cardiomyopathies. MiR-712 is a potential predictor of atherosclerosis, has blood flow-dependent expression, and miR-712 is also upregulated in endothelial cells exposed to naturally occurring d-flow in the greater curvature of the aortic arch [18]. Several studies have investigated the cooperation of miRNA, metalloproteinases (MMP), and tissue inhibitor of matrix metalloproteinases (TIMP) in aorthopathy secondary to morphological alteration of the aortic valve. miRNAs related to dilation of the thoracic aorta (TA) are upregulated in transcriptional and epigenetic ways: different levels of MMP-2, MMP-9, TIMP-1, and TIMP-9 were observed [19]. A high level of MMP-2 and increased levels of miR-17 and miRNAs with the same genetic features as miR-17 were found in a comparative study involving patients with mild and severe aorta dilation, with a decreased level of TIMP -1, TIMP-2, and TIMP-3, thus hypothesizing a continuous development of TA influenced by BAV [20]. A recent study showed a relationship between miR-133a and TIMP-1 and TIMP-2 without reporting a statistically significant association between miR-143 and MMP-2 [21].
Table 2. Gene expression involved in valve and aortic diseases. ACTA 2: alfa actine 2, AXIN: gene encodes a cytoplasmic protein that contains a regulation of G-protein signaling (RGS) domain and a disheveled and axin (DIX) domain, BAV: bicuspid aortic valve, ENG: Endoglin, FBN1: fibrillin 1, GATA (sequence for transcription factors for zinc proteins’ binding DNA sequence), NOS3: nitric oxide synthase 3, NOTCH1 (gene encoding transmembrane proteins), PDIA2: protein disulfide isomerase family A member 2, PECAM-1: platelet endothelial cell adhesion molecule-1, TGF: transforming growth factor, TIMP: tissue inhibitor of matrix metalloproteinases.
Plasma exosomal miR-423-5p regulates TGF-β signaling by targeting “similar mothers against decapentaplegic Drosophila gene” 2 (SMAD2), exerting functions in the initiation and development of BAV disease and its complication, bicuspid aortopathy [22,23]. Circulating miRNAs may reflect remodeling processes in the proximal aorta in patients with bicuspid aortopathy, and a recent study found a significant association between miRNA expression in peripheral blood and aortic tissue, as levels of miR-21, miR-133a, miR-143, and miR-145 were associated with dilated aorta [24].
Since abnormalities in vascular smooth muscle cells (VSMCs) may influence the development of TA dilation, primarily when contractile function converts to secretory function, this molecular situation causes cell apoptosis, in which the role of miRNA regulation may play a crucial role. Specifically, the convex part of ascending thoracic aorta (ATA) in BAV has increased miR-146-5p and miR-21-5p and reduced miR-133a-3p levels [25]; miR-424-3p and miR-3688-3p are downregulated in Hippo, ErbB, and TGF-beta signalling pathways, an epiphenomenon of cell proliferation and apoptosis [26]; and, finally, endothelial cells may have alterations due to abnormal flux patterns and genetic factors. This last alteration results in a less resistant vessel wall and can start a process of aortic dilation. Moreover, miR-494 is associated with platelet endothelial cell adhesion molecule (PECAM) and microparticles derived from endothelial cells [26], and the decreased expression of the miR-200 group can determine the involvement of the miR-200 family in endothelial–mesenchymal/epithelial–mesenchymal transition (EndMT/EMT) [27].
Observing the role of miRNAs as aortopathy biomarker of aortic dilation and increasing aortic dilation, it has been observed that miR-133a has a special linkage with the aneurysms’ incidence [28]; miR-122, miR-130a, and miR-486 are expressed in BAV; and miR-718 is used to predict aneurysms [29] similar to miR-34a [30].
Fibrillin 1 (FBN1) mutations have been found in BAV and aortic dilation. This gene encodes a glycoprotein of extracellular matrix (ECM), which manteins elastic fibers, and is also involved in the linkage of epithelial cells to interstitial matrix. A downregualtion of this gene has been associated with BAV [31]. GATA (sequence for transcription factors for zinc proteins’ binding DNA sequence) variations are involved in BAV: a missense p. Arg202Gln in GATA5 and three synonymous variants—p. Cys274 and p. His302 in GATA4, and p. Asn458 in GATA6 [32]. Alterations in nitric oxide synthase 3 (NOS3) are also associated with BAV. A single nucleotide polymorphism (SNP) is present in aneurysmal and non-aneurysmal BAV [33]. A haplotype within the AXIN-1-protein disulfide isomerase family A member 2 (AXIN1-PDIA2) locus and in the Endoglin (ENG) gene has been found to be linked to BAV [34]. Cilia and excyst have a main role in regulate mitogen-activated protein kinase (MAPK) signaling. An alteration of this mechanism is the cause of an activation of MAPK and the formation of BAV and calcified aortic stenosis [35].

3. Classification and Nomenclature

Since 1970, several classifications of BAV, derived from pathology, US scan, CT scan, and MR patterns (Table 3), have been proposed [36]. Recently, an international consensus statement developed a classification based on the progression of cusps fusion and geometry of commissurae [37], with particular attention to surgical indications and techniques.
Table 3. BAV classifications (adapted from Michelena HI et al./European Journal of cardio-thoracic surgery). Abbreviations; BAV, bicuspid aortic valve; BAVCon, bicuspid aortic valve consortium; LN, left non-coronary fusion; RL, right–left fusion; RN, right non-coronary fusion.
From this consensus statement, three BAV patterns related to the fusion of cusps and the number of sinuses may be observed. Every pattern should be considered like a schematic-based US short-axis scan at the base of the heart; the ideal circumference of the aortic valve is subdivided into parts like the face of a clock, in which the points over the watch are the coordinates of the anatomical features of the BAV.
In normal cardiogenesis, endothelium-derived nitric oxide syntethase (eNOS) expression is related to endocardial cells and is dependent upon the shear stress [48,49]. Nitric oxide is the promotor of podokinesis. In this way, cardiac jelly is populated by endocardil cells to make endocardil cushions [50]. In a study on mice, eNOS deficency may cause an alteration of cell migration with impairment in the development of valvular cushions, and an alteration of the function of cardiac neural crest cells has a role in this pathogenetic pattern [7,51].
The first pattern related to embryological events is defined as the fused bicuspid aortic valve (Figure 1) and diagnosed in 90–95% of cases [44] and presents three subtypes defined according to the cusps involved.
Figure 1. Fused bicuspid aortic valve. (A) Represents short-axis normal tricuspidal aortic pattern with anatomical proximities. Cusps’ fusion patterns seen in short heart axis: right-left coronary fusion (B), right-non coronary fusion (C). All BAVs have three sinuses. Raphe structure is between the fused cusps. Non-fused cusp is prominent in respect to the fused ones. The commissure angle of the non-fused cusp has a degree < 180°. Abbreviations: LA, left atrium; LC, left cusp; LCA, left coronary artery; MV, mitral valve; NC, non-coronary cusp; PA, pulmonary artery; RA, right atrium; RC, right cusp; RCA, right coronary artery; RV, right ventricule; TV, tricuspidalic valve. Licenses Centre Cardiologique du Nord; order date 8 September 2022; order number 5384080341542; publication NEJM; Title: Mitral valve Repair for Mitral valve prolapse.
In normal conditions, valve cushions are modelled by an excavation process resulting in fusion of the cusps in case of process alteration [51,52,53,54,55]. It is possible to distinguish three sinuses and the fusion of two of the three cusps. In contrast, the non-fused cusp commissure has an angle of different degrees and generally is more prominent than the fused cusps, as occurs for its sinus compared to the other two sinuses. A fibrous raphe, a predictor of further development of AS [56] between the two fused cusps, has been frequently observed [40,57]. The right–left cusp fusion, observed in 70–80% of patients [58] and often associated with AS and aortic regurgitation (AR) [44], is derived from a mild alteration in the outflow tract septation during embryogenesis and is linked to the formation of aneurysms in every section of the aorta (aortic root, ascending aorta, aortic arch) and frequently characterized by root dilation. An association has also been observed between right–left cusp fusion and aortic coarctation. The right–left cusp fusion is common in genetic syndromes, such as Turner’s one and Shone’s complex and people with Down syndrome [59]. In 20–30% of BAV cases, a proper non-coronary cusp fusion is present, more common among the Asian population [60] and frequently associated with AS in adults [56].
Moreover, it may be observed combined with an alteration of the process involved in the formation of the endocardial cushion, an independent predictor of AR [61]. In children, this phenotype may induce a more rapid development of AS and AR [62,63]. Left non-coronary cusp fusion is only present in 3–6% of patients [37].
The second type of BAV is referred to as the two sinuses BAV type (Figure 2).
Figure 2. Two-sinus bicuspid aortic valve. Figure represents two cusps’ non-fusion patterns seen in the short heart axis. Aortic valves have two sinuses with two leaflets non-derived from fusion mechanisms. (1) Coronary arteries originate from the two sinuses with two lateral leaflets. The opened valve in systole phase has the oval-ball image. (2a) In this position, coronary arteries originate from the anterior sinus (right coronary artery) and posterior sinus (common left stem). (2b) Right coronary artery and common left stem both originate from anterior sinus. Abbreviations; A, anterior; L, lateral P, posterior.
Its incidence ranges between 5 and 7% of cases [40,44,64]. In this pattern, it is possible to identify two cusps corresponding to homologous sinuses, not depending upon fusion but upon the abnormal embryological constitution. Typically, the cusps are the same in size, a raphe is not present, and the aortic orifice is divided into two portions: laterolateral (Figure 2(1)) and anteroposterior (Figure 2(2a,2b)). In the laterolateral pattern, coronary setup is from each sinus; in the anteroposterior type, coronaries may originate from each sinus or the anterior one. Embryological alteration involved in the laterolateral pattern is secondary to abnormal endocardial cushion formation and positioning. The aetiology of the anteroposterior model is due to abnormal outflow tract septation. The same mechanism in the fused aortic bicuspid valve type is present in this second morphological pattern, but the two-sinus valve may constitute a more severe embryological development alteration [37].
The third BAV type is a partial fusion bicuspid aortic valve (Figure 3), with an unknown prevalence [65].
Figure 3. Partial fusion aortic valve. Figure represents three cusps with partial leaflets fusion seen in the short heart axis (left). In this case, the opened (right) aortic valve is similar to the normal valve but with a more narrow area.
Morphological features are similar to a tricuspid valve with symmetry of the cusps, and the aortic orifice area is less comprehensive than the normal surface. A raphe is localized at the base of each commissure, causing a fixed portion of the cusp to the artic wall. For this reason, this phenotype is also called form fruste aortic valve [66,67,68]. An alteration of normal embryological processes may be identified. Therefore, it is assumed that a mild defect in outflow tract septation and remodelling of aortic valve cushions are present.
The above classifications (Table 3) have implications for daily clinical practice. Siever’s classification is still the most important for diagnosis and surgical indication. The classifications with the determination of the leaflets and the fusion patterns of the commissures are crucial for the development of aortic dilatation [69]. Even aortic valve morphology, flow changes, and prognostic evaluation are well determined by models derived from fusion pattern classification.

4. BAV Geometry Types and Surgical Implications

In every subtype of the previous classification, we can identify the BAV geometrical pattern by evaluating the position of commissures related to the aortic orifice, their angle in the coaptation zone, the presence of raphe, and the morphology and the area of the cusps. In the fused BAV type, it is relevant to establish the relationships between the fused cusps and non-fused cusp and the angle of the commissures of the non-fused cusps (Figure 4).
Figure 4. Symmetry of fused bicuspid aortic valve (adapted from Michelena HI et al./European Journal of cardio-thoracic surgery). Figure represents the angles determined by aortic valve leaflets fusion patterns. The length of raphe causes the retraction of fused leaflets and the non-physiological coaptation of the non-fused leaflet with fused leaflets. The geometry of the three patterns can be summarized as symmetrical, asymmetrical, and very asymmetrical The degree of the angle is important for surgical technique.
When the two fused cusps are retracted over the raphe, AR may develop. Therefore, the coaptation line and angle must be described mainly for surgical indications and practice. The coaptation angle may vary from 180° to less than 150°; to ensure a higher probability of valve repair, the ideal angle should range between 180° and 160°. When the angle approximates 140°, valve sparing and repairing is more complex [70]. Pre-cardiopulmonary bypass transoesophageal echocardiography establishes the coaptation model and commissural angle.
The two-cusp fusion model, more frequent in AS, has the two cusps/two sinuses feature, and the commissural angle is nearly close to 180° [37]. In partial fusion, the commissural angle resembles the one present in the normal aortic valve.
Surgical valve-preserving techniques are indicated by the commissural geometry of the aortic valve, as mentioned by a recent paper that also considers the relationship of the aortic root from the virtual basal ring (VBR) to the sinitubular junction [71].

This entry is adapted from the peer-reviewed paper 10.3390/jcm11206002

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