Ascending Aortic Aneurysm in Relation to Aortic Valve Phenotype

*David Freiholtz, Per Eriksson and Hanna M. Björck*

### **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) [4–6]. 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 [7–9]. 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

#### **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. [10]. (B) Immunohistochemical stainings of CD4+ cells in ascending aortic tissue of BAV- and TAV-patients, magnification x40. Adapted from Folkersen et al. [11].*

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.

#### **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/βcatenin, 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, 18–22]. Defects in these signaling pathways may indeed lead to dysfunctional valvulogenesis and the formation of a BAV [15].
