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Aortic Root Involvement in Congenital Heart Defects
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In: Perspectives in Aortic Valve Disease ISBN: 978-1-53618-769-4
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Editor: Giovanni Concistrè © 2020 Nova Science Publishers, Inc.
Chapter 9
ADULT BICUSPID AORTIC VALVE
Alessandro Della Corte* and Federica Lo Presti
Department of Translational Medical Sciences,
University of Studies of Campania “L. Vanvitelli”,
Unit of Cardiac Surgery and Transplant, Monaldi Hospital, Naples, Italy
ABSTRACT
Bicuspid aortic valve (BAV) is the most common congenital defect of the heart,
occurring in 0.5-2% of live births. It is estimated to be responsible for a relevant burden
of valvular and vascular disease in the adulthood (bicuspid valvulo-aortopathy). The
present chapter focuses on the aspects of valvular morbidity (aortic valve stenosis,
regurgitation, endocarditis) and complications of the thoracic aorta in the adult (aortic
dilatation, aortic dissection), trying to underscore similarities and unique features of
BAV-related conditions compared to the respective diseases in tricuspid aortic valve
patients. Epidemiological aspects, pathogenetic theories, risk stratification strategies and
treatment principles will be briefly reviewed.
Keywords: bicuspid aortic valve, aortic valve stenosis, aortic valve regurgitation, infective
valve endocarditis, aortopathy, aortic aneurysm, aortic dissection
INTRODUCTION
Bicuspid aortic valve (BAV) is the most common congenital defect of the heart,
occurring in 0.5-2% of live births and uniquely predisposing the subject to chronic or acute
complications either in infancy or in adulthood [1]. Most cases are isolated, non-syndromic
conditions, however the BAV can also be a part of complex clinical disorders, including
Turner syndrome (about one third of Turner patients have a BAV), Shone complex, LoeysDietz syndrome, etc. generally diagnosed in pediatric age [2]. Notably, even the nonsyndromic forms of BAV carry risks not only related to the aortic valve, but also to the
*
Corresponding Author’s Email: aledellacorte@libero.it.
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thoracic aorta: BAV is indeed best defined as a peculiar valvulo-aortopathy. This chapter will
focus on the implications of BAV in adulthood, therefore the main phenotypic expressions
and valvulo-aortic diseases occurring in the isolated non-syndromic forms will be the object
of the following paragraphs.
PHENOTYPES OF BICUSPID AORTIC VALVE
A BAV is defined as an aortic valve with two instead of three functional cusps, as a result
of congenital “fusion” or “non-separation” of two underdeveloped leaflets [1]: according to
which cusps are involved by the malformation, different types of BAV can result (Figure 1).
Traditionally, BAV morphological phenotypes (or morphotypes) are referred to according to
the Sievers classification [3], which takes into account the number of raphes and the pattern
of cusp fusion. The number of raphes defines the main category, being type 0 without a raphe
(“pure” bicuspid valves), type 1 with one raphe (the most frequent, accounting for nearly 90%
of cases) and type 2 with two raphes (better termed as unicuspid valves). The pattern of cusp
fusion defines the first sub-category: type 0 encompasses all circumferential orientations of a
BAV, among which either antero-posterior or latero-lateral variants exist, due to fusion of
right- and left-coronary cusps (RL) or right- and non-coronary cusps (RN), respectively.
Among type 1 BAVs, the most frequent pattern of fusion is the RL (nearly 70%), followed by
RN (15%) and the rarer LN (around 3%). Notably there seem to be differences in those
prevalence figures according to ethnicity: in particular the RN and LN forms seem more
frequent in Asian ethnicities compared to the western people [4]. Although widely employed
for several years this classification is only simplistically descriptive and has been criticized as
not useful in clinical and surgical practice: several attempts have been made to systematize
the morphological variability of the BAV with clinically-oriented methods, i.e., in radiology
[5], in interventional cardiology [6], in reparative surgery [7]. A consensus of experts has
very recently agreed upon a new classification of the BAV, which avoids misnomers (e.g.,
type 0 BAV for unicuspid; “true” BAV for the valve with 2 leaflets and 2 sinuses) and
indicates the different categories with descriptive denominations in English language rather
than with numbers and letters (unpublished).
Figure 1. Computed tomography scans of: A) a normal tricuspid aortic valve (R= right coronary cusp, L= left
coronary cusp, N= noncoronary cusp); B) a congenital bicuspid aortic valve of the RL morphotype; C) a
congenital bicuspid aortic valve of the RN morphotype. Note the relative dimesions of the cusps: the nonfused cusp (N in panel B and L in panel C) cover a larger surface area than they would in the normal tricuspid
aortic valve whereas the fused cusp is the result of two underdeveloped cusps joint together.
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Embryogenesis and Hemodynamic Effects of Different Morphotypes
A study carried out in adult and embryonic hearts of eNOS knock-out mice and inbred
Syrian hamsters, animal models with a high incidence of RN- and RL-type BAV,
respectively, presented evidence suggesting that different genetic substrates could underlie
the diverse valve morphotypes [8]. RN-BAVs could be the product of a defect occurring
before the left ventricular outflow tract (LVOT) septation, probably due to an exaggerated
NO-dependent endothelial to mesenchymal transition, whereas RL-BAVs could result from
the anomalous septation of the proximal outflow tract, likely due to neural crest cells
disorders [8]. However, a subsequent large cross-sectional study of BAV human families
found that the 2 most frequent BAV morphotypes could be interchangeably inherited within
the same family, with a morphologic concordance of nearly 70% in family members [9].
Therefore, it remains likely that different dys-embryogenetic mechanisms underlie the
different valve morphotypes, but the genetic bases could overlap, and inheritance could be
complex and multigenic.
Four-dimensional flow magnetic resonance imaging (4D flow MRI) studies highlighted
differences in ascending aortic flow directions and severity of derangements among different
valve fusion patterns. RL-BAVs give rise to a helical jet flow directed toward the right
anterior aortic wall [10], with higher axial WSS at the aortic root and proximal ascending
[11]. The RN-BAVs, instead, generate a flow jet initially directed toward the posterior aorta
[10], with higher circumferential WSS in mid and distal ascending aorta related to more
severe rotational flow [11]. Cusps fusion pattern and valvular dysfunction can also affect the
severity of flow derangements: in RN-BAVs there are more severe flow abnormalities and
larger aortas than in RL-BAVs, as well as in valvular stenosis compared to regurgitation [12].
Different Inherent Risks?
Whether the abovementioned different morphotypes of BAV imply different risks of
valve or aorta complications has been investigated in several studies. The RN type was
reported to be associated with more rapid progression towards aortic valve stenosis in the
pediatric age [13]; others have confirmed the higher frequency of BAV stenosis and lower
frequency of BAV insufficiency in patients with the latero-lateral orientation of the cusps or
RN-coronary fusion [14, 15].
Clinical follow-up investigations have yielded contrasting results regarding the
differences in aortopathy risk between the two main morphotypes: in a pediatric population
the RN type was significantly associated in univariate analysis with faster growth of the
ascending aorta (not confirmed however in multivariable analysis) [16]. However, according
to another study enrolling adult BAV patients, the RL type was a predictor of greater velocity
of size increase over time [17]. Such investigations might have been jeopardized by the
inclusion of a limited number of phenotypic variables: Della Corte et al., by including among
the explored covariates also the aortic phenotype (pattern of dilatation of the aorta) found no
significant association of either valve morphotype with faster growth of the aorta, whereas the
root phenotype (aortic dilation predominantly at the sinuses, with normal or less dilated
ascending tract – a phenotype in which the valve is almost exclusively of the RL type) was a
significant predictor [18]. So far the evidence on associations of the BAV morphotypes with
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different risk of aortopathy is considered inconclusive; once aortopathy develops, however,
there is unique association of the RL type with more proximal localization of the dilatation
and of the RN type with more distal involvement (possibly extending into the proximal arch):
the consistency of these findings with the different patterns of post-valvular flow and
interaction of flow with the aortic wall with different morphotypes, as reported above, is
striking [19, 20].
BICUSPID AORTIC VALVE STENOSIS
Although echocardiographically normo-functional, in most BAVs the two cusps exhibit
asymmetric anatomy and therefore asymmetric systolic excursion, generating geometrically
abnormal transvalvular-flow patterns (systolic transvalvular jet not parallel to the vessel’s
axis), causing an intrinsic degree of subclinical stenosis: the tangential forces exerted on the
aortic wall, namely wall shear stresses (WSSs), are uneven compared to the normal laminar
flow [12, 21, 22].
Once diagnosed, the BAV requires echocardiographic follow-up, with shorter intervals
between subsequent controls once valve dysfunction has developed. Since in BAV subjects
the LVOT diameter is larger than in TAV counterparts and ejective jets may be particularly
eccentric, guidelines recommend to estimate the severity of the stenosis by exploring the
transaortic peak velocity and mean gradient in multiple windows, whereas valve area
represents a secondary parameter [23].
Currently, the available knowledge and tools to predict progression of BAV stenosis
remain limited, although an echocardiography-based valve degeneration score, taking into
account calcification, thickening and mobility reduction, proved to predict need for surgery in
the follow-up, thus identifying a higher-risk subgroup of patients who may require more
frequent assessments [24]. Further computed tomography-based indexes or genetic tests could
be helpful in the future in predicting the evolution of an initially borderline valve function
[25].
BAV is a Relevant Cause of Aortic Valve Stenosis
In the majority of adults with a congenital BAV, the malformation is sooner or later
complicated by valve dysfunction necessitating aortic valve replacement (AVR), reported to
be necessary in 53% of patients within 25-years of diagnosis [26]. Calcific aortic stenosis
(AS) represents the most common fate of a BAV [24, 27], typically occurring earlier in life
than in a TAV subject [28]. As a consequence, after age-matching, BAV-AS patients exhibit
lower prevalence of systemic cardiovascular risk factors than TAV-AS subjects [29]. In
causing the predisposition of a BAV to AS, possible mutations affecting valve tissue array
and calcium deposition, e.g., those in the NOTCH1 gene [30] and intrinsically increased
leaflet stress and turbulent flow [12, 21, 22] may trump the effect of further acquired and
modifiable cardiovascular risk factors. However, total cholesterol and hypertension have been
found associated with AS onset in BAV patients [31]. The mechanisms of AS progression,
including inflammation, calcium deposition and ossification are shared between BAV and
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TAV patients [32]. Despite higher transvalvular gradient with a similar degree of valve
stenosis, BAV-AS patients exhibit lower degree of cardiac impairment, in terms of diastolic
function, stroke volume, left ventricular ejection fraction, left atrial size, and pulmonary
hypertension, than TAV-AS counterparts [29]. A subgroup of BAV patients may exhibit early
valve degeneration, i.e., calcification, thickening and decreased mobility, independent of
valve hemodynamics: in this subgroup, the risk of AVR at 12 years is as high as 70% [24].
AVR for AS represents the second most common cardiac operation in the adult
population, preceded only by coronary artery bypass grafting. Data from a large study of
adults undergoing aortic valve replacement for stenosis underscored the great contribution of
BAV condition to the epidemiology of AS, inasmuch as congenitally malformed aortic valves
are slightly more frequent than normal tricuspid ones, at least in male patients [33]. In
younger patients unicuspid valves are more prevalent: only 15% of patients requiring surgery
under 60 years had a TAV, conversely representing the majority (52%) of stenotic valves in
older patients [33].
Invasive Treatment of BAV Stenosis
Surgical treatment of BAV-AS follows current guidelines for the management of valvular
heart disease, which do not distinguish between TAV and BAV [23, 34]. However, as already
mentioned, the BAV population faces severe AS and subsequent surgery one or two decades
earlier than TAV subjects, implying longer exposure to prosthesis-related complications (e.g.,
prosthetic infective endocarditis, degeneration of biological prostheses, valve thrombosis and
so on) and greater impact on lifestyle (e.g., physical activity or sports, lifelong anticoagulant
therapy for mechanical prostheses, and so on) [25].
Notwithstanding the younger age at operation, early outcomes of aortic valve
replacement (AVR) for BAV patients are similar to those for tricuspid counterparts, in terms
of both in-hospital/30-days mortality and complications [35, 36]. Long-term outcomes in
BAVs are satisfactory too, with a reported 15-years survival after isolated valve surgery
ranging between 68% and 78% [35, 37], with no substantial difference after age-matching
with TAVs [35]. The good long term results are probably in part explained also by BAV
stenosis patients receiving on average larger size prostheses, due to their inherent larger
LVOT dimensions, thus making patient prosthesis mismatch, associated with poorer
outcomes after AVR [38, 39], a relatively uncommon condition [29]. BAV women
undergoing AVR present more frequently with AS and with more advanced AS than BAV
men [40]. Although they often receive smaller prostheses, associated with higher
transvalvular gradients and lower degrees of ventricular postoperative remodeling [41], shortand long-term outcomes after AVR in women are similar to men [40].
Transcatheter aortic valve replacement (TAVR) has widespread as a therapy for severe
symptomatic AS in tricuspid patients whose risk with conventional surgery was deemed high
or unacceptable [42, 43]. An usually asymmetric annulus and an uneven distribution of
calcium in the setting of BAV stenosis [44] led to the exclusion of BAV patients from both
TAVR trials [43] and current guidelines recommendations [23, 34, 45], due to concerns of
possible noncircular deployment of the prosthesis and consequent dysfunction.
Although initially off-label TAVR procedures in BAV patients resulted in higher
incidence of valve malposition and malfunction, significant paravalvular leaks (PVL), more
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conversion to surgery, more pacemaker requirements and less overall procedural success than
conventional surgery [46], there is mounting interest in improving TAVR outcomes in BAVAS patients, given the lowering of age and surgical-risk class thresholds for transcatheter
procedures in tricuspid counterparts. Recent analyses, however, confirmed lower device
success and higher rates of PVL - with a clear reduction by latest generation device implant
[47, 48, 49] -, similar in-hospital/30 days mortality compared either with TAVR performed on
TAV-AS [47, 48] or with surgical AVR [48]. CT-angiography remains the gold standard for
careful annulus analysis and TAVR planning [50, 51]. Further studies are warranted to
compare long-term efficacy and safety of transcatheter vs conventional replacement.
BICUSPID AORTIC VALVE REGURGITATION
Minimal degrees of aortic regurgitation (AR) are common among congenitally BAV
subjects. Pure AR was reported as significantly less common than stenosis (30% vs 70%) in
echocardiographic cohorts [46], as well as in surgical and autoptic series [52]. Nonetheless, a
purely regurgitant BAV with a dysfunction severe enough to require surgery is known to
cause almost the 7% of AVR due to primary AR, i.e., not secondary to aortic
dilatation/dissection or endocarditis [53]. In TTE examinations, the parasternal long axis view
can show in diastolic frames how one or both cusps prolapse, usually generating a hypereccentric AR jet. Alternatively, secondary AR can be identified as a central jet associated
with dilatation of one or more of the valve-root complex components, including the annulus,
one or more sinuses, and the sino-tubular junction.
The Regurgitant BAV
BAV patients affected by pure degenerative aortic regurgitation have unique clinical
features: the majority of them are males [54], taller and younger than those who suffer from
AS [55, 56, 57], more often with a RL cusp fusion pattern, whereas the aorta is commonly
affected by dilatation mainly involving the sinuses of Valsalva, in the so-called “root
phenotype” [58].
Once valvular dysfunction reaches thresholds for surgical treatment [23], the valve
should be replaced or, when feasible in experienced centers repaired: pre-operative
echocardiography plays a pivotal role in assessing reparability of the regurgitant BAV [46]
and today several preoperative measurements of the valve-root complex configuration can
predict the durability of the repair.
Principles of BAV Repair
At the beginning of the BAV repair experience, excellent short-term results were reached,
however in mid-term follow-up a relevant incidence of recurrent regurgitation was recorded
[59, 60, 61]. Repair techniques for regurgitant BAVs and valve-preserving surgery for BAVrelated aneurysms have evolved considerably over the past 20 years: nowadays, most non-
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calcified BAVs are preserved or repaired – even more frequently than TAVs –, with a
cumulative reoperation incidence of 20% at 15 years when combined with root surgery [62].
The improvement in repair results was achieved by means of both accurate understanding
of pathogenetic mechanisms and identification of morphologic predictors of reparability,
leading to more standardized and reproducible correction of all pathologic components of
valve and root at the time of surgery [63, 64]. The most important mechanisms underlying
BAV regurgitation are [65]:
cusp prolapse, almost always of the fused cusp, sometimes involving also the non-
fused cusp, possibly as a result of long-standing regurgitation;
annular dilatation;
root dilatation (sinuses, sino-tubular junction).
Free margin plication of the prolapsing cusp represents a milestone in BAV repair,
already introduced in the early 90’s [59]. Over the years, it became clear that the
underestimation of the extent of prolapse (e.g., of both fused and non-fused cusp) and the
intraoperative finding of an insufficient cusp tissue amount were among the reasons of repair
failure and/or withdrawal. Therefore, echocardiographic and intra-operative measurements
were introduced of both cusp geometric height, useful to assess the amount of leaflet tissue
available as repair substrate, and cusp effective height, useful to quantify the amount of
prolapse independently of each leaflet [66, 67].
Aortic annular stabilization/reduction is also fundamental to improve the durability of
repair, and it is mandatory with an annular diameter exceeding 26-27 mm [68, 69, 70].
Subcommissural plication sutures [69] have been quit in favor of annuloplasty performed by
either circular suture [68] or external ring [70] or of valve-sparing reimplantation.
Whenever the aortic root is enlarged, its replacement is necessary, either with valve
reimplantation or root remodeling completed with annuloplasty [71, 72]. Some Authors
suggested lowering the threshold for aortic root replacement in this setting to a diameter
exceeding 42-43 mm [63].
Recently, with the spreading of the repair techniques and the increased experience of
reference Centers, the anatomy of the regurgitant BAV has been more and more recognized to
encompass a spectrum of different morphologies, from the symmetric BAV with two sinuses
and two seamless cusps, through the BAV forms with two underdeveloped and fused cusps
and one non-fused cusp, to the more asymmetric forms with incomplete raphe in the fused
cusp [7, 73]. The symmetry of the two cusps (evenness of the respective portions of total
valve surface area covered) has been quantified as the angle of commissural orientation (CO),
whereas 180° indicates the symmetric BAV with two equally sized cusps [7]. The height of
the sub-commissural triangle below the raphe or pseudo-commissure is lower than the one of
the normal commissures: this height decreases with increasing symmetry of the valve
configuration. Also, the annulus (virtual basal ring) is more circular in the symmetric forms,
more elliptic in the asymmetric ones [73]. Symmetrical valves benefit from cusp plication
alone, asymmetrical BAVs may need commissural re-orientation towards 180° during root
surgery [74, 75], whereas the very asymmetrical BAVs are probably best treated as TAVs.
In patients presenting with cusp retraction/perforation, calcification of the raphe or a very
asymmetric BAV, the choice should tend towards AVR rather than repair [76]. However, in
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treating a BAV-AR, surgeons must keep in mind that survival after repair is similar to that of
gender- and age-matched BAV controls [77, 78].
ENDOCARDITIS OF THE BAV
Infective endocarditis (IE) is a rare but serious disease involving heart valves, with high
morbidity and mortality. Patients with structural abnormalities of cardiac valves, such as
BAV, are known to be exposed to a higher risk of IE. Although the linearized incidence of
endocarditis in BAV adults is low, about 0.3%/year in several estimates [24, 79], the high
BAV prevalence within the adult population implies that adequate attention must be paid to
the risk of infective complications of BAV.
Indications for Prophylaxis, Risks and Treatments
Published systematic reports of clinical features and surgical treatments of IE in adults
with BAV have been few [80, 81]. Patients with IE on BAV are younger, with less
comorbidity [82, 83] and more frequently male [84] than TAV counterparts. A multicenter
study estimated in BAV subjects a 23-fold higher adjusted relative risk (RR) of aortic valve
IE than TAV subjects [83].
Based on the risk of both IE and its complications, predisposing cardiac conditions are
officially classified as low-, intermediate-, and high-risk. Currently, IE antibiotic prophylaxis
(IEAP) is recommended by guidelines only for high-risk conditions, which do not include the
BAV [85, 86]. Some investigators showed higher rates of IE from either verified viridans
group streptococci etiology or suspected dental origin in a BAV subgroup than in the
remaining endocarditis patients [87], whereas others authors observed a lower incidence of
Sthaphylococcus aureus infection in BAV IE [83]. Several studies underscored a higher
frequency of perivalvular abscess in the BAV IE group compared with the TAV IE group
[82-84]. The underlying mechanism for this phenomenon remains unclear. However, the high
frequency of BAV cusps calcifications possibly extending to the perivalvular area and the
histologic derangements occurring in the BAV aortic media might explain an increased
susceptibility to infection spreading to the structures adjacent to the valve, resulting in a
perivalvular abscess and/or mycotic root involvement [84]. Perivalvular involvement is a
known factor increasing postoperative mortality in surgery for IE [88], only in part explained
by a greater technical complexity of the operation, that has to include abscess cavity opening,
draining and repairing [84]. Notably, in multivariate analysis, BAV was the only independent
predictor associated with an increased risk of aortic perivalvular abscess [84]. The
observation of a clinical profile similar to that of high-risk IE patients suggested to reconsider
the case for IEAP in BAV subjects [87]: anyway, the recommendation is still being debated
[89, 90]. BAV IE patients are 2-fold likely to undergo valve replacement than TAV IE
counterparts within the 5 years subsequent to the onset of the disease [83]. Prompt diagnosis
leads to timely surgery, that might prevent the formation and extension of perivalvular
abscess.
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