With an incidence of 7.6 per 100,000 persons, thoracic aortic aneurysms (TAA) are a common aortic pathology, and the 19th leading cause of death in the United States [1, 2, 3]. Traditionally defined as dilatation of the aorta to $\ge$1.5 times its normal diameter, TAA are largely asymptomatic and often diagnosed as incidental findings on unrelated routine imaging procedures. Over time, TAA can lead to adverse aortic events (AAE), which are often lethal complications such as dissection and rupture. Genetic predisposition, hypertension, hemodynamic forces, smoking, atherosclerosis, and pregnancy are all contributing risk factors of TAA pathophysiology [4]. While most TAA occur as isolated pathologies, they can develop as a consequence of aortic valve (AV) disease; either acquired Aortic Insufficiency (AI) and/or aortic stenosis (AS), or congenital, with the most common being Bicuspid Aortic Valves (BAV).

Aortic insufficiency, or regurgitation, occurs when AV integrity is compromised due to inadequate leaflet closure. Characterized by diastolic blood flow reversal from the aorta into the left ventricle (LV), AI leads to progressive LV dilation and eventual heart failure if left untreated. Frequently encountered with TAA involving the aortic root [5, 6, 7], AI is a relatively common condition with a 13% male and 8.5% female prevalence [8]. In contrast, AS pathophysiology resembles atherosclerotic disease (lipid accumulation, inflammation, fibrosis, and calcification), where leaflets progressively stiffen, reducing blood efflux, causing pressure overload and LV myocardial hypertrophy [9, 10]. Affecting 3–5% of people $>$65 years of age, AS severity and prevalence increases with age [11]. Compared to normal or sclerotic AV (early stage AS), AS is associated with an increased incidence of dilated ascending aortas [12].

BAV occur in 1–2% of the population, carry a 3:1 male predominance [13], and are the most common congenital heart defect [14]. Until recently, there has been no consensus on the nomenclature and classification of different BAV types, with numerous heterogeneous classification systems causing confusion [15, 16]. With international consensus, congenital BAV are now classified into one of 3 major types (Fused BAV, 2-Sinus BAV, and Partial-fusion BAV), each with specific phenotypes (Fig. 1, Ref. [15]). As a congenital condition with strong genetic ties, BAV are associated with manifestations in tissues beyond the AV, including: aortopathies, aortic valvulopathies (AS and/or AI), additional congenital cardiovascular abnormalities, coronary anomalies, and other genetic disorders [17, 18]. Specifically, mutations associated with BAV development also impact aortic architecture, increasing susceptibility to TAA formation and dissections, while altered hemodynamics across bicuspid shaped AV further contribute to aortic dilatation. AV disease also develops much earlier in BAV, with AS occurring most frequently ($>$70%), followed by AI (15–30%), and mixed AI/AS (20%) [15, 18].

Fig. 1.

Schematic of the three major BAV types with associated phenotypes. BAV types as seen by short-axis transthoracic echocardiogram. (Top Row) Fused BAV type is the most common with 3 phenotypes named according to cusp fusion pattern. A raphe may not always be visible or present, however all fused BAV have 3 distinguishable aortic sinuses, with the non-fused cusp typically being the largest. (Middle Row) 2-sinus BAV is uncommon, does not have a raphe, and is characterized by 2 cusps of nearly equal size and shape, each occupying 180° of the circumference and has only 2 distinguishable aortic sinuses. Relative cusp orientation dictates phenotype as either latero-lateral or anteroposterior. Coronary arteries arise from each cusp (1 and 2A) or both from the anterior cusp in the AP phenotype (2B). (Bottom Row) Partial-fusion BAV (or forme fruste) is characterized by the presence of a short cusp fusion (50%) at the base of a commissure in an otherwise normal appearing tricuspid aortic valve with 3 symmetrical cusps. Abbreviations: A, anterior; BAV, bicuspid aortic valve; IAS, interatrial septum; L, latero-lateral; LC, left coronary cusp; NC, non-coronary cusp; P, posterior; RC, right coronary cusp; RV, right ventricle; TV, tricuspid valve. Reproduced and modified with permission from the authors [15].

Given the asymptomatic nature of TAA, serial surveillance after diagnosis using various imaging techniques like echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) is crucial. However, accurately predicting disease progression and the risks of AAE in TAA patients, especially when there is concurrent AV disease, remains exceedingly challenging. Currently, there is no comprehensive approach in managing patients with AV disease and TAA that incorporates all imaging techniques and necessary knowledge concerning AV disease-TAA pathophysiology; an approach essential to providing accurate disease prognosis and appropriate monitoring in these patients.

This review aims to summarize the latest scientific knowledge on the link between AV disease (AI, AS, BAV) and aortopathies of the proximal aorta (root/ascending), as well as identifying current gaps in the management of TAA patients with AV disease. We hope the manuscript will set the stage for further research to better address these complex conditions that existing clinical tools and methodologies fail to do.

The most proximal portion of the aorta is known as the aortic root, starting with the anatomical crown-shaped annulus of the AV cusp insertion points or virtual basal ring, followed by the ventriculoaortic junction, the AV leaflets housed within the sinus of Valsalva, and ending with the sinotubular junction (STJ). From there, the ascending tubular aorta begins and courses until the aortic arch, defined as the takeoff of the innominate artery. Normal mean aortic root diameters range from 3.50 to 3.91 cm (smaller in women) and taper in the ascending aorta to 2.7 and 3.0 $\pm$ 0.4 cm in women and men with tricuspid aortic valves (TAV) respectively. By convention, an arterial aneurysm is defined as any artery dilated to at least 1.5$\times$ its expected normal diameter [19], and although this definition works for aneurysms of the descending and abdominal aorta, we now know it fails when defining aneurysms of the root and ascending aorta [20].

When determining if an aortic root or ascending aorta is aneurysmal, the most important consideration to account for is the natural history of abnormal aortas in these locations, specifically the relationship between aortic diameters (+/– presence of BAV) and the incidence of adverse aortic events, as guideline recommendations for surgical intervention are based on this. By evaluating the risk of type A dissections below the traditional 5.5 cm threshold for prophylactic aortic repair, Paruchuri et al. [21] found that when compared to control aortic diameters of 3.4 cm, aortic diameters between 4 and 4.4 cm conferred an 89-fold increase in relative risk of dissection, and those $\ge$4.5 cm carried a 6000-fold increase. Consequently, the most recent 2022 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for the Diagnosis and Management of Aortic disease now define dilatation of the root or ascending aorta as diameters between 4.0–4.4 cm and aneurysms as those with diameters $\ge$4.5 cm [20]. This definition is also now consistent with that proposed by the 2014 European Society of Cardiology aortic disease guidelines [22].

For patients whose height and weight are significantly different from the average population ($\ge$1–2 standard deviations $\pm$ mean), it is important to normalize aortic diameters in order to accurately differentiate between normal and dilated/aneurysmal aortas. Various normalization methods exist, including aortic size index (ASI) and height index (AHI), where the ratio of aortic diameter to body surface area (ASI) or height (AHI) is calculated [23, 24]. Another commonly used method utilizes the cross-sectional area (CSA) of the aorta, rather than aortic diameter, to normalize aortic size to height [25]. These measures are frequently used in clinical practice for adult patients with TAA, as they have been shown to be more reliable predictors of AAE than diameter alone [21, 22, 23]. Consequently, the most recent ACC/AHA guidelines recommend using indexed aortic measures, including ASI $\ge$3.08 cm/m${}^2$, AHI $\ge$3.21 cm/m, and CSA to height ratio $\ge$10 cm${}^2$/m, as new thresholds for surgical intervention [20].

The formation and particular location of an aneurysm can both influence and be influenced by AV morphology and pathology. In AS, altered blood flow through a stenotic valve leads to a forceful ejection jet, altered hemodynamics, and mechanical stresses on the aortic wall distal to the stenosis. This is ultimately associated with proximal aortic dilation and aneurysm formation, in a concept known as post-stenotic dilation [26, 27, 28]. The extent of this relationship is even more apparent in patients with BAV and AS, so much so, that this phenomenon is defined as BAV–associated aortopathy. BAV–associated aortopathy most commonly affects the tubular ascending aorta, occurring in up 60–70% of BAV patients [29, 30], and is greatest with right-left (RL) coronary cusps are fused, followed by right-non (RN) coronary cusp fusion [31, 32]. Interestingly, within the BAV population, aortic dilation is present in 40% of patients regardless of the presence of AI/AS, raising the possibility of genetic or pathological changes related to the development of BAV that also lead to aortic wall weakness and aneurysm formation [29, 33, 34]. The relative contribution of hemodynamic forces and genetics to the development of BAV-associated aortopathy remains debated [29, 35], with both factors likely contributory.

Conversely, aneurysms involving the STJ, sinuses of Valsalva, and/or aortic annulus often result in the development of AI (Type 1a-c), where the AV leaflets are pulled apart and no longer able to coapt (Fig. 2, Ref. [36]). Since AI is associated with aortic dilation, a vicious cycle of worsening AI and aneurysmal degeneration can ensue. With progressive dilatation of the aortic root, the AV leaflets become stretched and irreversibly damaged, leading to leaflet fenestrations, cusp prolapse [36, 37, 38, 39], and worsening AI.

Fig. 2.

Repair-oriented functional classification of AI with disease mechanism and repair techniques. Abbreviations: AI, aortic insufficiency; FAA, functional aortic annulus; STJ, sinotubular junction; VAJ, ventriculoaortic junction. Reproduced and modified with permission from the authors [36].

The natural history and risk profile of an aneurysm change drastically whether associated with TAV or BAV, as well as the presence of AS or AI. On one end of this spectrum, TAV-AS aneurysms tend to be slow-growing with more stable aortic walls, whereas, on the other extreme, BAV-AI aneurysms are particularly aggressive (Fig. 3). Between these, less is known about the effects of TAV-AI and BAV-AS on TAA development, and while not as dangerous as BAV-AI, both are prevalent and remain dangerous [27, 37, 38, 39, 40, 41, 42].

Fig. 3.

Proposed Spectrum of TAA formation risk in the presence of AV disease. Abbreviations: AV, aortic valve; AI, aortic insufficiency; AS, aortic stenosis; BAV, bicuspid aortic valve; TAA, thoracic aortic aneurysm; TAV, tricuspid aortic valve.

3.2 Bicuspid Aortic Valves and TAA

Unlike TAV disease, aneurysms associated with AI vs AS in patients with BAV have been well studied. With a higher prevalence of aortic dilatation, more severe pathological aortic remodeling, and a higher probability of adverse aortic events, BAV-AI patients possess the worst clinical course compared to BAV-AS and functionally normal BAV [37, 39, 42, 44, 45]. This is due to a combination of (i) increased hemodynamic burden secondary to the increased stroke volumes in AI, and (ii) intrinsic abnormalities found in the aortic walls of BAV patients leading to fragility [27]. Patients with BAV-AI are more often male and younger than BAV-AS [37, 46], and usually associated with root dilation (root phenotype) compared to predominantly tubular ascending aortic dilation in BAV-AS patients [38, 47, 48]. Echocardiography data from the early 1990s showed BAV-AI was associated with a higher prevalence of aortic annular (59% vs 9%) and sinuses of Valsalva dilatation (78% vs 36%) when compared to BAV-AS, while 60–65% of both groups had ascending aortic dilation [48].

Similarly, Sievers et al. [38] also demonstrated associations of BAV-AI with root/ascending dilation and BAV-AS with eccentric ascending aortic dilation. Notably, even BAV patients with only trace AI were still significantly associated with root/ascending aortic dilatation, emphasizing the more aggressive aortopathy phenotype found in BAV-AI [38]. Expanding on this, Della Corte et al. [47] poignantly showed BAV-AI to be predictive of root dilation (odds ratio (OR) 3.9), while BAV-AS was predictive of mid-ascending aortic dilation (OR 23.8) and protective of root dilation (OR 0.26). Furthermore, the frequency of aortic replacement at time of BAV surgery is significantly higher with BAV-AI patients when compared to BAV-AS patients (35% vs 17%, (p 0.001) [37, 38].

Interestingly, the configuration of BAV cusp fusion has also been shown to influence resultant valve dysfunction type (AI vs AS) and aortopathy phenotype. Using the Sievers classification system for BAV phenotype, Sievers et al. [38] demonstrated stenotic BAV (type 0 and type 1 RL) to be significantly associated with more localized aortic dilatation (ascending only), whereas insufficient BAV type 1 RL tended to involve the root and showed more extended aortopathy (root and ascending aorta). Categorizing BAV type based on orientation of the free edge of the cusp, Kang et al. [49] found AI significantly more prevalent in anterior-posterior vs RL configuration (anteroposterior (AP) 32.3% vs RL 6.8%, p 0.0001), while AS was more common in RL vs AP (66.2% vs 46.2%, p = 0.01). Comparing aortopathies, these authors found BAV-AP was more common in normal aortas or aortic root dilation (type 0/1 aortopathy), and BAV-RL with ascending or ascending/arch dilation (type 2/3 aortopathy) (Fig. 4, Ref. [49]). Completing this interconnected triangle, AI was significantly more common in type 0/1 aortopathy (32.9% vs 10.2%, p 0.0001), and AS with aortopathy type 2/3 (64.8% vs 44.3%, p = 0.002) [49]. Since, RL fusion as defined by Sievers (type 1 RL) was included in Kang et al.’s [49] AP group, and RN (Sievers type 1 RN) was part of their RL group, both studies correlate well and show a strong clinical connection between BAV cusp configuration, valvular pathology, and aortopathy phenotype.

Fig. 4.

MDCT images representative of BAV aortopathy phenotypes. Bicuspid aortopathy phenotype is dependent on the pattern of BAV dysfunction, including both anatomical BAV configuration and the presence of AI or AS. Three distinct phenotypes have been identified, including: Type 0—normal aorta, Type 1—dilated aortic root only, Type 2—involvement of the tubular portion of the ascending aorta, and Type 3—diffuse involvement of the entire ascending aorta and transverse aortic arch. Reproduced and modified with permission from the authors [49]. Abbreviations: AI, aortic insufficiency; AS, aortic stenosis; BAV, bicuspid aortic valve; MDCT, multi-detector computed tomography.

Current criteria for concomitant aortic replacement when undergoing surgery for AV dysfunction is 4.5 cm, irrespective of AV anatomy or dysfunction type, holding a Class 2a recommendation for both TAV and BAV [20]. As such, this recommendation fails to account for the increased risks of TAA formation and adverse aortic events seen with BAV patients, as well as type of valve dysfunction present. This recommendation was largely based on a small study of 200 patients by Borger et al. [50], where they demonstrated a significantly increased risk of aneurysm, dissection, or sudden death (p 0.001) in BAV patients with aortic diameters between 4.5 to 4.9 cm, compared to those with aortas 4.5 cm at 15 years following AVR. However, this study did not assess the associations of AI or AS on these outcomes.

With the same 4.5 cm recommendation for prophylactic aortic replacement as TAV, a significant cohort of already at risk BAV patients with dilated aortas are left behind, who may be at even higher risk depending on the presence of BAV-AI. Comparing BAV-AI to BAV-AS patients post-surgical AVR, BAV-AI patients showed faster rates of aortic dilation (0.29 mm/yr vs 0.18 mm/yr, p 0.001) and increased occurrence of adverse aortic events (15.5% vs 4.5%, p = 0.018) [39]. BAV-AI is an independent predictor for adverse aortic events even after AVR, with patients showing a 10-fold higher risk of dissection than BAV-AS patients post AVR (2.8% pooled estimate of dissection rate vs 0.2%), with increasing risk seen with smaller aortic diameters in BAV-AI patients [42]. Despite these findings, both groups demonstrated similar long-term survival [51], likely due to the overall low numbers of observed adverse aortic events.

Altered blood flow through aneurysmal aortas cause hemodynamic changes that affect the aorta, even in the absence of AV disease (AS, AI, or AS/AI) or abnormal AV morphology (BAV). With the advent of 4D MRI, a great deal of research in fluid dynamics has been produced, as blood flow through the heart and great vessels over an entire cardiac cycle can now be evaluated [52]. As expected, 4D MRI of TAV-TAA patients has demonstrated wall shear stress (WSS) reduced by 21% to 33% across most regions of dilated aortic walls relative to non-dilated aortas [53]. Holding stroke volume constant, mean velocity gradients are reduced in the presence of an enlarged vessel, which in turn reduces WSS [54]. The reduced pressure gradient is secondary to aberrant flow within the dilated aorta, where the incidence and strength of supraphysiologic helix and vortex flow correlates with increased ascending aortic diameter [55]. Moreover, systolic time to peak velocity and extent of retrograde flow both increase with increasing aortic diameter, leading to reduced flow efficiency in TAA [56].

Several studies have demonstrated altered flow dynamics in AS to impact the aortic wall [53, 57]. Bauer et al. [57] compared patients with BAV-AS to those with TAV-AS, and demonstrated no differences in aortic root diameter between groups, however the peak systolic wall velocity in the anterolateral region of the aortic wall was higher in BAV-AS than TAV-AS [36]. Within BAV-AS, velocity was higher in anterolateral than the posterolateral location [57]. However, these authors did not have a BAV group with no stenosis, so it remains unclear whether this difference was due to BAV phenotype alone. To isolate these confounding factors, van Ooij et al. [53] analyzed BAV and TAV patients with and without AS. In mild stenosis, TAV patients with TAA go from decreased WSS to increased WSS along the outer portion of the ascending aorta. As stenosis progresses to moderate or severe, impaired valve opening leads to more pronounced high velocity jets with marked increase in regional WSS.

Remarkably, differences in WSS location between BAV and TAV dissipated when the degree of AS was moderate/severe, implying AS as the now dominant factor governing hemodynamics, as well as it being a contributing factor in TAA formation [53]. How this altered flow affects aortic growth over time would require longitudinal imaging studies, which have yet to be performed. In addition, flow dynamic studies assessing TAA formation in the presence of AI are lacking in both TAV and BAV patients [58].

Aside from genetic components implicated in the development of BAV-associated aortopathy, altered hemodynamics play a large role in TAA formation in both TAV and BAV patients. These effects are more pronounced in BAV patients and also vary depending on the presence of AI or AS. In contrast to TAV, where a central flow jet directs blood flow parallel to the aortic wall, BAV usually produce eccentric outflow jets [53, 59, 60, 61] which is consistent with the asymmetric aneurysmal formations characteristic of BAV [62]. Compared to TAV, averaged WSS is elevated in BAV irrespective of aneurysmal formation or valvular pathology [59, 63]. Flow displacement (eccentric jets) is higher in BAV and is predictive of aortic growth rate, with dilation rates up to 1.2 mm/yr in patients with markedly eccentric flows relative to 0.3 mm/yr in BAV patients with les flow displacement [64, 65]. BAV have decreased cusp opening angles (a measure for BAV opening restriction), which causes systolic flow deflection toward the right anterolateral ascending wall [66]. This measure also independently predicts ascending diameter and growth rate in non-dilated aortas.

Like wall shear stress, the concept of wall principal stress (WPS) is an important factor in understanding the mechanical behavior of TAA, and also differs between BAV and TAV. In contrast to WSS, WPS denotes the location of maximum aortic wall shear stress, and is perpendicular to the direction of blood flow rather than parallel [58, 61, 67]. Irrespective of AV type, WPS is greater along the inner aortic wall when compared to the outer wall, with local WPS maxima occurring just above the STJ (Fig. 5, Ref. [61]) [68]. It is at this location that an aortic wall is mostly likely to tear or rupture, secondary to the discontinuities in stress at the interface between aortic layers [61]. This is supported by clinical observations noting this location as the most common origin site of type A dissections [61, 69]. Lastly, with respect to valve type, BAV aneurysms exhibit higher severity WPS at all locations when compared to TAV [61], which may account for the increased risks of dissection among patients with BAV [33, 70].

Fig. 5.

Computational FSI analysis for inner and outer maximum WPS in ATAA patients with TAV and BAV. Both TAV and BAV patients demonstrate higher inner WPS compared to the outer aortic wall, with local maxima of WPS occurring just above the STJ (inset image). BAV patients display slightly higher stresses than TAV patients (36.5 N/cm${}^2$ vs 29.4 N/cm${}^2$), suggesting a greater risk of aortic dissection. Reproduced and modified with permission from the authors [61]. Abbreviations: ATAA, ascending thoracic aortic aneurysm; BAV, bicuspid aortic valve; FSI, fluid structure interaction; N/cm${}^2$, newton per centimeter squared; STJ, sinotubular junction; TAV, tricuspid aortic valve; WPS, wall principal stress.

Further complicating the hemodynamic role in BAV is the recognition that cusp fusion phenotype changes the outflow jet orientation and flow abnormalities, impacting the aorta and the WSS parameters [53, 60, 71]. The two most common cusp fusion types found in BAV is RL fusion, followed by RN coronary cusp fusion. Blood flow through BAV-RL occurs as right-handed helical flow, with right-anterior flow jets, whereas right-non-coronary (R-NC) has more severe flow abnormalities, and gives rise to a left helical flow and left-posterior or right-posterior flow jet [60, 71, 72]. These differences lead to different areas of aortic WSS. BAV-RL aortas have peak WSS along the right-anterior ascending aorta [59, 60], or increased WSS at the root and along the entire outer curvature of the aorta [53]. In contrast, BAV-RN leads to peak WSS along the right-posterior aorta [60], or increased WSS at the distal portion of ascending aorta [53]. These differences correlate well with clinical presentations associated with cusp fusion phenotype, namely RL fusion being associated with a root dilation phenotype, and RN with distal ascending aorta dilation and often root sparing [53].

Flow alterations are more pronounced, and different from each other, when assessing the combined effect of BAV and the presence of AS or AI. Shan et al. [59] observed that compared to control BAV, BAV-AI patients had universally elevated WSS and correlated with stroke volume. BAV-AS patients had elevated flow eccentricity, as the accelerated flow velocity from the AS exacerbated the already eccentric flow found with BAV. However, the location of peak WSS at the right-anterior ascending aorta, was similar regardless of AI or AS, as was the associated aortopathy, mainly type 2. Since this study focused solely on BAV R-L patients, the location of peak WSS was likely due to this phenotype rather than AI or AS [59]. As such, further studies correlating the effects of valve dysfunction type (BAV-AI and/or AS) on altered hemodynamics and not just cusp fusion phenotype are needed. In addition, longitudinal imaging studies comparing the impact of AI and AS flow dynamic on the aortic wall are needed to help explain the observed differences in natural histories of aortopathies in the presence of AI vs AS.

With an abundance of evidence, it is clear that AV structure and function greatly influences the integrity of the aorta. The association between AS and TAA, as well as AI and TAA in the setting of TAV or BAV has been thoroughly confirmed. However, the exact mechanisms through which each valvular anomaly contributes to aortic dilation and aneurysm formation remain unclear. While examinations of AV and aortic anatomy, have revealed similarities in cellular and extracellular matrix compositions, the extent to which TAA pathogenesis in the setting of AS/AI is caused by genetic alterations (heritable gene mutations causing aortic wall fragility), or altered hemodynamics (WSS), or both, continues to be a debate.

Despite remarkable progress in the past few years in the understanding of the pathophysiology of TAA, the exact causes and pathways underlying the phenotypic differences observed in AS/AI and TAV/BAV TAA patients remain undefined. This is likely due to the multifactorial nature of such diseases, where genetic and hemodynamic factors together dictate the fate of disease progression.

Lineage tracing analyses using reporter genes, and studies of conditional knockout animal models have revealed the presence of common cellular origins contributing to the formation of both the ascending aorta and the leaflets of the AV (smooth muscle cells derived from the secondary heart field and cardiac neural crest cells) [86, 87, 88]. Whether this common cellular origin plays a contributing role in the pathophysiology of TAA remains to be answered.

Endothelial cells represent the interface between blood and the aortic wall and valve. As such, these cells are the first to be exposed to shear stress generated by blood flow. Changes in shear stress can lead to changes in endothelial cell gene expression and function, with different responses observed when laminar flow versus oscillatory flow have been tested on these cells [89, 90]. Interestingly, laminar shear stress induced differential responses in porcine endothelial cells derived from the aortic wall to those derived from the AV [91] and transcriptional differences have been highlighted between these two cellular populations [92]. More research focusing on understanding human endothelial cells and smooth muscle cells derived from the aorta and the AV, as well as the implications of BAV genetic background, should be undertaken to help explain the clinical variability that we see on imaging. This knowledge will help bridge the gap and integrate our clinical understanding with the findings from basic science which may help in the management of patients with TAA and AV disease.

Current guidelines for aortic replacement in TAA do not account for the presence or type of AV dysfunction when determining aortic size thresholds for surgery [20, 110], and vice versa, with AV disease guidelines providing no recommendations for aortic interventions during AV surgery depending on valve dysfunction type [111]. Specifically, prophylactic repair of TAA is recommended at $\ge$4.5 cm if undergoing AV surgery, irrespective of whether the valve is bicuspid or tricuspid, regurgitant or stenotic [20, 112]. Developing a framework to understand the impact of valvular dysfunction on TAA formation, with clinical implications on surveillance, both before and after surgery, and need for surgery itself, is critical. This review clearly demonstrates epidemiological and clinical phenotypes connecting AI in both TAV and BAV with major adverse aortic events, as well as more rapid rates of TAA growth. Patients with AI are at increased risks of developing aortopathy at younger ages, increased risks of root dilation, rapid rates of TAA growth—both before and after AVR, and carry a greater risk of adverse aortic events (Tables 1,2). These risks are further exacerbated in patients with BAV-AI compared to TAV-AI. Furthermore, in addition to the already increased hemodynamic burden from AI on the aortic walls, AI patients have universally elevated WSS and more severe medial degeneration with elastin loss and fragmentation, further weakening the aortic wall.

As such, AI patients (especially BAV-AI) should be followed more aggressively, both preoperatively and postoperatively following AVR for AI in the presence of mildly dilated proximal aortas. It is clear after analyzing all available data in the literature, that AI patients with aortopathy (dilation/aneurysms) represent a different risk group than those with AS or normal functioning AV. Unfortunately, with no current guidelines recognizing this special at-risk subgroup, these patients are improperly categorized into the general AV/TAA pathology population who are at lower risk of aortic dilatation and adverse aortic events.

Comprehensive aortic surveillance programs should not only include longitudinal anatomic analysis of the aortic root and ascending aorta via computed tomography (CT)/MRI scan, but also morphologic and functional analysis of the AV by echocardiography. Only then can we accurately perform risk assessments with fully informed data for these patients. Other non-invasive measures for improved assessments of aortic wall integrity should also be sought, with possible avenues of research to include biomarkers and improved imaging techniques.

A paradigm shift in the management of patients with AI irrespective of valve morphology is in order. Additional longitudinal research examining how the degree of AI impacts the risk of aortic dilatation and adverse aortic events will help strengthen this new framework and should be the first step. Longitudinal definition of the progression of AI with focus on the ascending aorta in BAV vs TAV will provide clearer guidelines for surgical intervention. Finally, further translational research will help identify the causes and pathways leading to TAA formation as a consequence of the distinct pathological AV phenotypes reported in this review.

HJ and DL contributed equally to the work. JG, HJ, DL, and GF designed the research study. HJ, DL, LG, CC, EC, and HT performed the research, interpreted the data, and wrote the manuscript. All authors contributed to editorial changes and revisions to the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

The authors wish to acknowledge the contribution of Jinan Jabagi, the medical illustrator who created the hand drawn images in Fig. 3.

This work was supported, in part, by the Cannstatter Foundation (to Valley Hospital Cardiac Surgery Department), the National Heart, Lung and Blood Institute of the National Institutes of Health (R01-HL131872) (to G.F.), and the Andrew Sabin Family Foundation Cardiovascular Research Laboratory (G.F.).

The authors declare no conflict of interest.