Bicuspid aortic valve (BAV) is a congenital heart disease characterized by the presence of two commissures, rather than the usual three[1]. BIt affects approximately 1-2% of the general population, making it the most common congenital heart disease [2]. The exact cause of BAV remains unclear, but it has been associated with various genetic syndromes and disorders, including Shone complex, Kabuki syndrome, and Marfan syndrome, as well as genetic variations and mutations ^[3][4][3,4].  Initially, BAV was thought to be a connective tissue disease like Marfan syndrome. However, subsequent observational and clinical studies have shown that BAV does not affect connective tissue to the same extent^[5][6][5,6]. Nonetheless, BAV patients still face a higher risk of aortic complications compared to those with a tricuspid aortic valve. A significant proportion of BAV patients requiring aortic valve replacement (AVR) or repair surgery also require concurrent aortic surgery due to BAV-associated aeropathy^[7][8][7,8]. Despite the high rates of aortic surgery in BAV patients, ongoing debate surrounds the threshold for concurrent aortic surgery based on aortic dimensions^[9][10][9,10].hese thresholds now vary, taking into account the genetic profiles of the patients and the characteristics of the aortic wall.

Despite being the most prevalent congenital heart disease, the aetiology and pathogenesis of bicuspid aortic valve morphology remain partially understood. However, the prevailing consensus within the literature suggests that this morphological condition is underpinned by a robust and intricate genetic basis.

The occurrence of BAV within families is notably 5 to 15 times more prevalent than in the general population, pointing towards a likely genetic basis for this correlation ^[11][16]. Importantly, the male-to-female ratio in cases of BAV is evenly distributed at 1:1, which contrasts with the gender patterns observed in numerous acquired heart conditions ^[11][16]. In a study by Boureau et al., in which they focused on patients with calcific aortic valve disease, it was revealed that isolated cases of calcific aortic valve disease were more likely to show tricuspid morphology. Conversely, cases of calcific aortic valve disease presenting in a familial pattern showed predominantly bicuspid valve morphology ^[12][17]. Emphasizing the criticality of the issue, Tessler et al. emphasized the importance of performing echocardiographic evaluation in first-degree relatives of individuals diagnosed with BAV ^[13][18].

Examining the congenital syndromes associated with BAV holds substantial significance in unravelling the formation and potential pathogenesis of BAV itself. As depicted in Table 1, the incidence of BAV within congenital heart diseases provides insightful data. For instance, a notable correlation exists between BAV and the Shone complex, a condition characterized by a defect in the myocardial structural protein (MYH6). Remarkably, approximately 9 out of 10 patients with the Shone complex exhibit BAV, which is a severe form of left heart structural abnormality. Additionally, BAV is present in about one-third of patients with ventricular septal defect (VSD), suggesting a possible link to neural crest cell migration processes. Particularly striking is the elevated prevalence of BAV in conditions such as Turner and Kabuki syndromes. These syndromes, known to disrupt valvular microenvironmental homeostasis due to genetic impairments, exhibit a prevalence of BAV exceeding 10 times that of the general population (21% vs. 2%). This recurrent presence of BAV in such syndromes underscores its intricate association with conditions involving compromised neural crest migration and gene abnormalities that potentially disrupt the valvular microenvironment ^{[14][15][16][17][18][19][20][21][22][23][24][25][26]}[19,20,21,22,23,24,25,26,27,28,29,30,31].

Table 2 presents a comprehensive overview of the genes associated with bicuspid aortic valve disease, believed to contribute to the development of this specific valve morphology ^{[27][28][29][30][31][32][33][34][35][36][37][38][39][40]}[32,33,34,35,36,37,38,39,40,41,42,43,44,45]. Upon closer examination of these genes and the pathways they participate in, alongside congenital heart syndromes commonly featuring BAV, the genetic foundation of BAV can be succinctly summarized as follows:

• Function and Dysfunction of Cardiogenesis-Polarization Genes: Notably, genes integral to cardiogenesis, such as GATA and NKX2-5, play a pivotal role. These genes are central to the establishment and proper functioning of the heart.
• Dysregulation of Genes Associated with Neural Crest Cell Migration: Genes like ROBO4, implicated in the regulation of neural crest cell migration, also feature in the genetic context of BAV. Dysfunction here might contribute to anomalies in cardiac development.
• Defects and Disorders in Genes Governing Valve Microenvironment Maintenance: The integrity of the valve microenvironment relies on genes like TGFB2 and TBX. Irregularities in these genes can potentially lead to disruptions in the microenvironment, affecting valve development.
• Gene Aberrations in Structural Aspects of Connective Tissues: Structural issues concerning connective tissues are influenced by gene disorders, including FBN1 deficiency. These genetic irregularities can give rise to problems in the structural integrity of tissues that constitute the cardiovascular system.

In essence, the genetic underpinnings of BAV encompass a complex interplay of various genetic factors and pathways. The intricate dance between genes related to cardiogenesis, neural crest cell migration, valve microenvironment maintenance, and connective tissue structure collectively shapes the development of BAV. This holistic understanding underscores the multifaceted nature of the genetic basis behind BAV’s manifestation.

Genetic factors play an important role in the formation of BAV morphology as well as in the development of related aortic problems. Specifically, when genes responsible for structurally regulating connective tissue encounter disruptions or when genes essential for maintaining the valve microenvironment experience dysregulation, the result is weakening of the aortic structure ^{[6][7][8][9][15]}[6,7,8,9,20]. While it is crucial to acknowledge that genetic anomalies are not the sole origin of aortic pathologies, they are acknowledged as a constituent aspect of the overall pathogenic process, shedding light on the complex interplay between genetic factors and the emergence of aortic complications.

Epigenetic factors have been suggested to contribute to aortic complications in patients with BAV. The non-linear blood flow across the BAV and its direction, which is influenced by the specific subtype category of BAV pathology, play a significant role ^[41][46]. The turbulent jet flow over the BAV increases wall shear stress on the valve and the associated areas of the ascending root and ascending aorta. Consequently, high wall shear stress leads to various epigenetic changes in smooth muscle cells, endothelial cells, and valvular interstitial cells. Increased wall shear stress triggers the expression of proinflammatory cytokines and proteins, potentially resulting in the thickening of valve cusps and degeneration of the aortic media. Studies by Rashad et al. have demonstrated the upregulation of pro-atherogenic factors (such as ICAM1 and E-selectin), pro-angiogenic factors (such as KFL2), and pro-vascular fibrotic factors (such as NOS) in response to high wall shear stress, as observed in patients with BAV ^[42][47].

The hemodynamic changes associated with BAV also contribute to the different types of aortic dilatation and aneurysm formation observed in BAV aortopathy. Arch dilatation is more common in patients with R-N cusp fusion, with jet streams directed toward the arch, whereas ascending aortic aneurysms are more prevalent in patients with L-R fusions, with jet streams directed toward the ascending aorta ^[43][48]. In a study by Charitos et al. involving 361 BAV patients and 448 patients undergoing tricuspid AVR, no difference in aortic dilatation or an increase in the size of the middle root was observed between BAV and tricuspid AVR patients after surgery. The authors concluded that aortic dilatation in BAV is primarily due to valve hemodynamics rather than genetic factors ^[44][49]. Fungi et al. reported a study involving 431 patients who underwent either isolated AVR, AVR with ascending aorta replacement, or aortic root replacement between 1993 and 2019. Their findings indicated that concomitant aortic surgery during aortic valve surgery for BAV does not impact survival in patients with BAV whose ascending aorta diameter ranges from 40 mm to 45 mm ^[45][50].

3. Aetiology and Significant Thresholds for Intervention

Epigenetic and genetic factors that contribute to the etiology of BAV and its associated conditions hold paramount importance in treatment planning for the disease. While the standard aortic intervention threshold is 55 mm, experienced centers may lower it to 50 mm for BAV cases. Furthermore, in patients undergoing AVR, this threshold may decrease to 45 mm. Additionally, factors like epigenetic influences and accompanying conditions such as aortic regurgitation and wall stress play a significant role in influencing this threshold. Moreover, specific genetic disorders implicated in bicuspid valve etiology have distinct cut-off values.

In clinical practice, aortic aneurysms are classified based on their diameter, which serves as a crucial indicator for determining the appropriate intervention. As the aortic diameter reaches the 40-45 mm range, genetic mutations in genes like TGFBR1, TGFBR2, and SMAD3 become particularly relevant in assessing the risk of aneurysm progression and rupture ^[46][84]. Expanding further to 45-50 mm, additional genetic factors including ACTA2, COL3A1, and FBN1 come into focus, significantly influencing the clinical course and management of aortic aneurysms ^[46][84]. This nuanced understanding of genetic factors at varying diameter thresholds empowers clinicians to make more precise and tailored decisions regarding the treatment and surveillance of patients with aortic aneurysms.

Threshold for Aortic Intervention	Genes	Reference
40-45 mm	TGFBR1/2 SMAD3	[46][84]
45-50 mm	ACTA2  COL3A1 FBN1	[46][84]