Introduction

The management of aortic valve disease has been transformed in the past 20 years by the rapid emergence of transcatheter aortic valve implantation (TAVI) which is now preferred to surgical aortic valve replacement (SAVR) in most high and intermediate risk patients with aortic stenosis (AS) and rapidly expanding in lower risk cohorts, particularly in mainland Europe and the USA.1 This evolution reflects the outcomes of pivotal randomised controlled trials comparing the two treatment modalities, although it should be emphasised that patients with bicuspid aortic valve (BAV) disease were excluded from almost all of these studies. In this review article, we address the timing of treatment, mode of intervention and means of follow-up in the challenging group of patients with BAV.

Epidemiology and genetics

BAV is the most frequent congenital heart disease, occurring in 1–2% of the overall population and accounts for up to 50% of patients referred for SAVR.2 The fact that BAV and associated aortopathy are also more common in men and people with the NOTCH 1 gene or XO Turner syndrome suggests a potential genetic and chromosomal predisposition.3 4

Anatomy and pathophysiologyBicuspid aortic valve morphology and associated aortopathy

Anatomical BAV phenotypes are conventionally described using the Sievers classification according to the number of raphes and subclassified according to cusp spatial position and functional valve status5 (figure 1A). Other classifications include the Schaefers classification based on leaflet morphology and the presence or absence of leaflet fusion6 (figure 1B) and the international classification recognising the transitional patterns of aortic valve.7

Figure 1

Anatomical patterns in bicuspid aortic valve disease. (A) The Sievers classification (prominent lines represent a raphe). The main categories are as follows: type 0 with no raphe; type 1 with one raphe; type 2 with two raphes, with the following subcategories: anterior-posterior (AP), lateral (lat), L-R, R-N, N-L and L-R/R-N. L, left coronary cusp; R, right coronary cusp; N, non-coronary cusp. (B) The Schaefers classification. Small inset top left depicts a normal aortic valve in the same orientation with right coronary cusp (RC), left coronary cusp, non-coronary cusp, right coronary artery and left coronary artery. Valve phenotypes: type 1, fusion between right and left coronary cusp; type 2, fusion between right and non-coronary cusp; type 3, fusion between left and non-coronary cusp.

Associated thoracic aorta dilatation is common with a prevalence ranging from 20% to 84%8 and typically affects the aortic root and ascending aorta (figure 2A). The rarer involvement of the arch and descending thoracic aorta indicates the distinct embryological origin of these different aortic segments.9 Regardless of location, several reports suggest that aortic root aneurysms in the setting of BAV have a more malignant and rapidly progressive course.10

Figure 2

(A) Contrast CT demonstrating post-stenotic dilatation of the ascending aorta in a patient with a bicuspid aortic valve and prominent greater curve. (B) Three-dimensional velocity streamlines showing trajectory of aortic flow velocity during peak systole. Higher velocity jets are represented in red. AR-TAV, aortic regurgitation tricuspid aortic valve; AS-BAV(RL), aortic stenosis bicuspid aortic valve with right-left cusp fusion; AS-BAV(RN), aortic stenosis bicuspid aortic valve right-non cusp fusion; AS-TAV, aortic stenosis tricuspid aortic valve; LCA, left coronary artery; RCA, right coronary artery.

The prevalence of aortic dilatation increases with age,11 and patients with BAV have an eightfold increase in the risk of aortic events compared with the general population.12 Although increasing aortic dimensions are associated with risk of aortic dissection, these measurements remain a poor prognostic predictor.13

Aortic flow dynamics in patients with BAV

Four-dimensional 4D flow MRI and computational fluid dynamic studies demonstrate that patients with BAV have prominent systolic flow patterns (especially in the ascending aorta) with exaggerated clockwise turbulent flow that persists into the descending aorta (figure 2B). In contrast, patients with trileaflet aortic valve demonstrate mild clockwise helical flow of blood as it travels around the aortic arch.14 15 These observations confirm that flow in the aorta of patients with BAV is more turbulent and is associated with increased wall sheer stress and higher flow displacement, which in turn may predict increased rates of growth in aortic diameter.16

Aortic stenosis and regurgitation

Premature BAV calcification results in abnormal leaflet motion and AS at younger age, with more rapid haemodynamic deterioration in comparison with trileaflet valves.17 Only 15% have a normally functioning valve by their fifth decade2 and associated AS is the most common indication for surgery. Isolated aortic regurgitation (AR) is typically seen in younger patients, those with root dilatation and minimal valve calcification18 and may relate to cusp prolapse, endocarditis, dilated aortic root and myxoid valve degeneration. Although AS and AR frequently coexist, AS is the predominant indication for isolated SAVR in approximately 60% and AR in 15–30%.12 Of note, endocarditis is seen in only 2% of patients with BAV, but outcomes are worse than in trileaflet valve cohorts.12

Rates of progression of AS and AR (and associated aortopathy) vary in individual patients and careful serial imaging surveillance in a dedicated valve clinic is essential. There are no evidence-based medical therapies, although beta blockers may be of value in reducing aortic wall stress and the rate of progressive aortic dilatation.19

Indications for intervention

Recommendations on indications for intervention in symptomatic and asymptomatic AS, severe AR and aortic root or tubular ascending aortic aneurysm (irrespective of the severity of AR) are well described in the 2021 European Society of Cardiology (ESC) / European Society for Cardio-thoracic Surgery (EACTS) guidelines for the management of valvular heart disease (table 1).19

Table 1

Recommendations on indications for intervention in symptomatic (A) and asymptomatic (B) aortic stenosis59

The mode of intervention

Patients with BAV and associated significant AS/AR are often younger and have a higher incidence of associated aortopathy. Evidence concerning the use of TAVI in this setting is limited, and patients with BAV were excluded from almost all the available randomised trials. The mode of intervention should therefore be determined by Heart Team discussion encompassing the likely outcomes of surgical or transcatheter intervention, the impact of associated aortopathy, anticipated life expectancy, bioprosthetic valve durability and aspects relating to overall lifetime management.

Surgical aortic valve replacement

Overall mortality of SAVR and SAVR+coronary artery bypass graft surgery in the UK database of 31 277 patients (including both BAV and trileaflet aortic valve cohorts) was 1.9% and 2.4%, respectively.20 If anything, surgical outcomes in suitable patients with BAV are superior to trileaflet valve comparators with in-hospital mortality ranging from 0.9% to 2.4% (table 2)21–24 and long-term outcomes comparable to those of the general population. Mechanical SAVR is associated with significant long-term mortality benefit particularly in patients younger than 55 years of age.25

Table 2

Outcomes of SAVR in patients with BAV

Transcatheter intervention

Less invasive intervention is generally preferred in older subjects or those at high risk for surgery and patients with BAV account for approximately 10% of the current TAVI population.26 Although this proportion is likely to increase substantially as TAVI is used beyond guideline recommendations in younger patients. BAV may be associated with anatomical features that make TAVI more challenging (including asymmetrical cusps, bulky asymmetric calcification, commissural fusion, concomitant aortopathy, anomalous coronary takeoff and horizontal annular alignment) despite advances in transcatheter heart valve THV) design and increased operator experience.27 These factors may be associated with suboptimal outcomes due to anatomical difficulties or technical factors. In particular, precise prosthesis sizing to ensure an accurate anatomical fit is more challenging owing to the ‘bizarre’ BAV anatomy, with heavily calcified leaflets, commissural fusion, calcific or fibrotic raphes, and slit-like elliptical orifices. Several algorithms for both annular and supra-annular device sizing have been proposed, although none is perfect and considerable experience in interpretation is required.27 Nevertheless, good results have been reported in several observational series, particularly in patients with BAV calcification that spares the valve leaflets and raphe.27 28

These technical challenges explain the findings of observational studies assessing the outcomes of TAVI in patients with BAV (table 3) that demonstrate good overall results across the spectrum of age and surgical risk, but a higher frequency of paravalvular regurgitation and permanent pacemaker implantation in comparison with trileaflet aortic valve cohorts.29–33 Consistent with these observations, recent findings of the NOTION-2 randomised controlled trial in all comers aged <75 years suggest that SAVR may remain a better overall option in younger, low-risk patients with BAV.34

Table 3

Outcomes of TAVI in patients with BAV

Ross procedure

This surgical procedure entailing replacement of the diseased aortic valve with a pulmonary autograft and placement of a homograft in the pulmonary position has several advantages, including avoidance of anticoagulation, lower rates of structural valve deterioration and very good long-term outcomes in small series from high volume experienced centres. However, the operation is not widely performed (<0.1% of all aortic valve operations in the US database) owing to its technical complexity (resulting in higher operative mortality) and potential long-term failure of two valves (when only one was originally diseased), exposing the patient to the possibility of high-risk re-do procedures over long-term follow-up. The Ross operation is not recommended in patients with aortopathy, connective tissue disease, a large aortic annulus, or mismatching aortic and pulmonary dimensions.35

Impact of associated aortopathy

International guidelines recommend concomitant aortic surgery or root replacement at the time of SAVR when the aortic diameter is ≥45 mm, regardless of the pattern of aortopathy or underlying BAV phenotype.36 Valve-sparing aortic root replacement can also be considered in patients with bicuspid aortopathy and relatively normal aortic cusps with good mobility, although long-term results and the likelihood of future valve failure remain uncertain. Timing of surgical intervention remains a key clinical decision. The timing should be at the point when risks during surveillance exceed the risk of surgical intervention. The primary aim of a prophylactic procedure is to avoid aortic dissection and rupture. The mean aortic diameter at the time of dissection was 10 mm greater in patients with BAV than in those with a trileaflet valve.37 Multiple studies have quantified the risk over time of development of dilatation of the ascending aorta (to a size of 4.0–4.5 cm). These studies indicate that 20% to 30% of patients with BAV develop aneurysmal enlargement during a follow-up of 9–25 years. One series suggested that approximately 84% of patients with BAV will develop an aneurysm and risk was found to be 80-fold higher than for the general population.38 Nevertheless (and despite these data), concomitant replacement of the ascending aorta is performed only in approximately 25% of patients with BAV.

Abnormal aortic flow patterns associated with BAV often persist after SAVR and may impact on subsequent progressive aortopathy.39 Some studies report that the aorta ceases to grow after SAVR,40 while others report conflicting findings.41 Careful follow-up is therefore required and it is reasonable to suggest CT or MRI of the entire aorta every 3–5 years after SAVR, even in the absence of residual aortic pathology.36

Durability of surgical and transcatheter bioprostheses

The life expectancy of the patient and the expected durability of the treatment should be of utmost importance when considering the optimal treatment of patients with BAV. A fit 50-year-old person living in a high-income country has a life expectancy of 34 years42 and a patient of the same age with a bioprosthesis (SAVR or TAVI) has a >30% likelihood of needing a second intervention.

There are well-documented data on durability of surgical bioprosthetic valves in both BAV and trileaflet valve patients. Pericardial valves, such as Perimount Magna Ease and Inspiris Resilia (Edwards Lifesciences, USA), have shown very good durability. In a series evaluating 2405 Carpentier Edwards aortic valves, the overall freedom from reoperation for prosthetic valve dysfunction was 98%, 96% and 67% at 5, 10 and 20 years, respectively.43 44

However, there are less data concerning the durability of THVs, particularly in large series. The NOTION trial compared TAVI and SAVR in lower risk patients with trileaflet aortic valves as well as BAV and showed no statistical difference for major clinical outcomes at 5-year and 10-year follow-up.45 The risk of the primary composite endpoint for patients with BAV was 14.3% and 3.9% after TAVI and SAVR, respectively. The rates of paravalvular regurgitation and pacemaker implantation were higher after TAVI. Importantly, despite the fact that balloon expandable THVs have higher radial force and lower ellipticity index than self-expandable devices, all TAVI valves may be potentially constrained and underexpanded in patients with BAV when compared with those with trileaflet anatomy.46 Given that underexpansion may impact THV durability and promote leaflet thrombosis, these findings have raised concerns about the possible acceleration of processes underlying structural valve deterioration in patients with BAV.47

Lifetime management

Decisions concerning the mode of intervention and type of prosthesis needed to address the potential risks of future repeat procedures in individual patients undergoing valve replacement with a bioprosthesis require special consideration by the Heart Team, particularly those with prolonged life expectancy. Possible options for future repeat procedures include TAVI within a previous SAVR prosthesis (TAV-in-SAV), repeat TAVI in a patient with a previous TAVI prosthesis (TAV-in-TAV), THV explantation combined with SAVR and re-do SAVR.

Valve-in-valve TAVI (TAV-in-SAV and TAV-in-TAV)

Valve-in-valve (ViV) TAVI is defined as transcatheter implantation of an aortic valve into either a previous TAVI or SAVR. Use of ViV TAVI as a treatment option for patients with a failing surgical bioprosthesis (TAV-in-SAV) is rapidly increasing as a consequence of the number of younger patients with prolonged life expectancy who receive a bioprosthetic valve at the time of index surgery (meaning that they outlive their valve), and this presents an excellent strategy for patients at high risk for re-do surgery.48 Reflecting this trend, current generation of surgical bioprostheses (such as the Edwards Inspiris; Edwards Lifesciences) have been designed with fluoroscopically visible size markers and an expandable cobalt-chromum alloy band to facilitate ViV TAVI and minimise the likelihood of procedural complications.49 A recent meta-analysis demonstrated that ViV TAVI was associated with reduced likelihood of 30-day mortality compared with re-do SAVR (OR 0.56, p<0.01), although with a higher risk of paravalvular regurgitation (OR 6.82, p=0.04) or severe patient-prosthesis mismatch (OR 3.77, p<0.0001).50 Randomised controlled trials directly comparing these two treatment strategies are needed and already underway.

The number of second-time TAVI (TAV-in-TAV) procedures is also set to increase dramatically in the coming years owing to the unexpected longevity of many first wave TAVI recipients and the rapid extension of TAVI to younger cohorts (particularly in some regions of the USA, where TAVI accounts for 48% of aortic valve interventions in patients with AS aged <65 years).51

Potential procedural challenges (that may be mitigated by careful CT-guided patient selection) include a higher risk of iatrogenic coronary artery obstruction (that may be addressed by leaflet laceration or splitting techniques), higher frequency of patient-prosthesis mismatch or need for permanent pacemaker implantation, thromboembolic potential (requiring prolonged antithrombotic treatment) and challenging future coronary access at the time of diagnostic angiography or percutaneous intervention (which may be difficult or impossible in some TAV-in-TAV recipients).52

THV explantation combined with SAVR

Surgical explantation of the THV is a rare and technically difficult procedure associated with increased risk of morbidity and an early mortality rate of 15–20%.53 54

Currently available data suggest that the procedure is only required in 0.4–1% of all TAVI recipients but rapidly increasing in frequency.54 The most common indications being severe paravalvular regurgitation (41.2%), structural valve deterioration (23.5%) and infective endocarditis (5.9%).55 56 Despite the relatively high risk of adverse outcome, THV explantation combined with SAVR may be a better option than a TAV-in-TAV procedure in patients at increased risk of severe patient-prosthesis mismatch or coronary obstruction.

Heart Team decision-making

Heart Team discussions concerning the lifetime plan of care for an individual patient with BAV should incorporate the following essential concepts: (1) SAVR and TAVI are complementary treatment approaches, (2) both may be required during the patient’s lifespan and (3) the presence and severity of aortopathy make an important contribution to decision-making (box 1).

Box 1 Key considerations for clinical decision-making in patients with bicuspid aortic valve stenosis

Surgery is the preferred option for patients with BAV, especially those who are young (<75 years, at low risk for surgery (STS score <4%), and with an aortic diameter >45 mm.

TAVI may be appropriate in older patients (≥75 years) with non-complex morphology and no associated aortopathy, and in those at high risk for surgery (STS score ≥4%).

Valve durability, life expectancy and the presence and severity of aortopathy should be at the centre of Heart Team discussions.

TAVI in a 50-year-old patient with a life expectancy of 30 years may expose them to the need for at least two further valve interventions (which may be associated with high procedural risk).

Although experience with TAVI explant is accumulating, the procedure carries significant risk when compared with re-do SAVR.

BAV, bicuspid aortic valve; STS, Society of Thoracic Surgery; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

Based on the rapid and appropriate expansion of TAVI, some may speculate that a patient in their mid-60s with favourable BAV anatomy and mild or moderate aortopathy (<45 mm) may be best treated with an initial TAVI procedure followed by a low risk SAVR (with or without aortic intervention) when the transcatheter heart valve deteriorates 10 years later, and a subsequent TAV-in-SAV procedure when the patient is in their 80s or 90s. However, while this approach is intuitively appealing, there are several caveats:

The mortality risk of initial SAVR in a younger patient is only 1–2%, but may be as high as 15–17% in later years.

A strategy of initial TAVI followed by future SAVR or ViV commits the patient to three sequential bioprostheses while avoiding only one sternotomy.

Initial SAVR allows the opportunity to deal with associated aortopathy and any other concomitant pathology (such as coronary artery disease).

Replacement of the root and/or ascending aorta following TAVI is technically challenging and experience remains limited.

The overall risk of first-time aortic root replacement is less than the cumulative risk of TAVI and subsequent aortic root replacement in patients with BAV-associated aortopathy from the outset.

Future developments

Earlier identification of patients with BAV, particularly those susceptible to aortopathy and early valve degeneration, is key and advances in genetic screening coupled with improved access to diagnostic imaging (echocardiography, CT and cardiac MRI) are important priorities. Future research should include dedicated randomised controlled trials directly comparing the use of SAVR and TAVI in patients with BAV, and studies aimed at identification of subsets with aortopathy who are at highest risk of complications. Building on initial cautionary messages from the NOTION-2 trial,45 the NAVIGATE-BICUSPID international multicentre randomised trial is set for initiation in late 2024 and will compare the use of SAVR and TAVI in 1500 all-comers with BAV AS, although it will be some years before outcomes are available. Meanwhile, dedicated TAV-in-TAV registries in Europe and the USA will allow increased understanding of the specific challenges associated with this treatment strategy and enlighten current discussions concerning the lifetime management of patients with BAV. Ultimately, advances in valve design that ensure optimal haemodynamics and leaflet durability may overcome the need for repeat procedures. TAVI is also emerging as an option for high-risk patients with pure AR, either using conventional devices ‘off-label’ or newly available dedicated valve systems.57 The JenaValve (JenaValve Technology, California, USA) was originally developed for transapical delivery but excellent results are now being obtained using an updated transfemoral system with high rates of device success and low frequency of paravalvular regurgitation in patients with tricuspid aortic valve.58

Conclusions

BAV disease affects 1–2% of the overall population and is frequently encountered in everyday clinical practice. Premature valve degeneration results in progressive AS and AR that are unresponsive to medical therapy, and patients with BAV account for up to 50% of the population undergoing aortic valve surgery. Concomitant aortopathy is also progressive with an associated risk of aortic dissection or rupture and careful imaging surveillance is essential. International guidelines provide clear recommendations concerning the thresholds for intervention and surgery remains the definitive treatment option, especially in younger, low-risk patients or those with significant dilatation of the root or ascending aorta. TAVI also has an increasingly important role in older high-risk patients (particularly those with an aortic diameter <45 mm) and randomised trials directly comparing surgical and transcatheter treatment strategies are keenly awaited. Meanwhile, Heart Team discussions concerning the optimal treatment for individual patients (guided by clinical and anatomical considerations) are essential, particularly when sequential procedures are anticipated over several decades.

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