Journal of Clinical Medicine Review Unraveling Bicuspid Aortic Valve Enigmas by Multimodality Imaging: Clinical Implications Arturo Evangelista Masip 1,2,3, *, Laura Galian-Gay 1 , Andrea Guala 1 , Angela Lopez-Sainz 1 , Gisela Teixido-Turà 1 , Aroa Ruiz Muñoz 1 , Filipa Valente 1 , Laura Gutierrez 1 , Ruben Fernandez-Galera 1 , Guillem Casas 1 , Alejandro Panaro 3 , Alba Marigliano 3 , Marina Huguet 3 , Teresa González-Alujas 1 and Jose Rodriguez-Palomares 1 1 Departament de Cardiologia, Hospital Vall d’Hebron.CIBERCV, Universitat Autonoma de Barcelona, 08035 Barcelona, Spain; lauragaliangay@gmail.com (L.G.-G.); andrea.guala86@gmail.com (A.G.); kelals@hotmail.con (A.L.-S.); gisela.tt@gmail.com (G.T.-T.); aroa.ruiz.munoz@gmail.com (A.R.M.); filipaxaviervalente@gmail.com (F.V.); lauraguga@gmail.com (L.G.); ruben.fernandez@vhebron.net (R.F.-G.); gcasasmasnou@gmail.com (G.C.); teresagonzalu@gmail.com (T.G.-A.); jfrodriguezpalomares@gmail.com (J.R.-P.) 2 Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain 3 Teknon Heart Institute-Quiron Salud, 08022 Barcelona, Spain; alejandro.panaro@quironsalud.es (A.P.); albamarigliano@gmail.com (A.M.); marinahuguet@gmail.com (M.H.) * Correspondence: arturevangelistamasip@gmail.com Abstract: Multimodality imaging is the basis of the diagnosis, follow-up, and surgical management of bicuspid aortic valve (BAV) patients. Transthoracic echocardiography (TTE) is used in our clinical  routine practice as a first line imaging for BAV diagnosis, valvular phenotyping and function,  measurement of thoracic aorta, exclusion of other aortic malformations, and for the assessment Citation: Evangelista Masip, A.; of complications such are infective endocarditis and aortic. Nevertheless, TTE is less useful if Galian-Gay, L.; Guala, A.; we want to assess accurately other aortic segments such as mid-distal ascending aorta, where Lopez-Sainz, A.; Teixido-Turà, G.; Ruiz Muñoz, A.; Valente, F.; computed tomography (CT) and magnetic resonance (CMR) could improve the precision of aorta Gutierrez, L.; Fernandez-Galera, R.; size measurement by multiplanar reconstructions. A major advantage of CT is its superior spatial Casas, G.; et al. Unraveling Bicuspid resolution, which affords a better definition of valve morphology and calcification, accuracy, and Aortic Valve Enigmas by reproducibility of ascending aorta size, and allows for coronary artery assessment. Moreover, CMR Multimodality Imaging: Clinical offers the opportunity of being able to evaluate aortic functional properties and blood flow patterns. Implications. J. Clin. Med. 2022, 11, In this setting, new developed sequences such as 4D-flow may provide new parameters to predict 456. https://doi.org/10.3390/ events during follow up. The integration of all multimodality information facilitates a comprehensive jcm11020456 evaluation of morphologic and dynamic features, stratification of the risk, and therapy guidance of Academic Editor: Micha Maeder this cohort of patients. Received: 7 December 2021 Keywords: bicuspid aortic valve; echocardiography; computed tomography; magnetic resonance Accepted: 13 January 2022 imaging; aortic aneurysm Published: 17 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Bicuspid aortic valve (BAV) is the most common congenital heart disease, with a reported prevalence of 0.8–1.5% [1,2] and a male predominance of nearly 3:1. It is considered to be a valvulo-aortopathy characterized by a large individual heterogeneity, both at the Copyright: © 2022 by the authors. valvular and aorta level, but also in the possible associated disorders, complications, and Licensee MDPI, Basel, Switzerland. prognoseis [3,4]. The most frequent complication of the BAV condition in adults is aortic This article is an open access article valvular dysfunction, more frequently in the form of severe aortic stenosis (AS), needing distributed under the terms and surgical aortic repair or AV replacement (AVR) (population-based 25-year risk of AVR is up conditions of the Creative Commons to 50%) [1]. The second most frequent complication, especially in those above 60 years-old, Attribution (CC BY) license (https:// is ascending aorta dilation. However, the important heterogeneity in terms of the pattern creativecommons.org/licenses/by/ of aortic dilation described in the complete BAV cohort is possible heterogeneity in the 4.0/). molecular, rheologic, and clinical features [5–9]. J. Clin. Med. 2022, 11, 456. https://doi.org/10.3390/jcm11020456 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 456 2 of 16 Early and accurate diagnosis of BAV and its complications by imaging techniques is essential to improve the management and outcome of BAV patients. Transthoracic echocardiography (TTE) is used in clinical practice for first line imaging for BAV diagnosis, valvular phenotyping and function, measurement of thoracic aorta, exclusion of other aortic malformations, and assessment of complications such are infective endocarditis and aortic dissection The aim of this review was to update the role of multimodality imaging techniques in BAV assessment, including recent advances and pending gaps. The main objectives of imaging techniques in the evaluation of this disease are: (1) BAV diagnosis; (2) phenotype description; (3) valvular function assessment; (4) ascending aorta dilation measurement; (5) exclusion of aortic coarctation; and (6), in some specific contexts, ruling out the presence of severe complications such as endocarditis and aortic dissection. In fact, multimodality imaging is the cornerstone not only in diagnosis, but it is also a relevant tool during follow-up of this congenital disease in order to evaluate the necessity of surgery intervention, and to assess post-surgical surveillance. Several classifications have been proposed for the BAV condition [9–17], most of which include multiple numbers and letters for the BAV and aorta phenotypes [9]. Recently, Michelena et al. published an International Consensus Statement on Nomenclature and Classification of BAV and its aortopathy [18]. This consensus recognized three types of bicuspid valve: the fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes), the two-sinus type (latero−lateral and antero−posterior phenotypes), and the partial-fusion (forme fruste) type. The authors point to the presence of raphe and the symmetry of the fused type phenotypes as the most important aspects to describe. The International Consensus also recognizes three types of bicuspid valve-associated aortopathy—the ascending phenotype, root phenotype, and extended phenotype. 2. Diagnosis and BAV Phenotype Transthoracic echocardiography (TTE) is the first imaging tool to diagnose the presence of BAV, given its accuracy in 80–90% of cases [1]. Nevertheless, there are some limitations we should take into account, like the extensively-calcified valve, poor visualization of the valve, or the distal ascending aorta. Other imaging techniques such as computed tomography (CT) or cardiac magnetic resonance (CMR) may solve these drawbacks. Transesophageal echocardiography (TEE) is also useful for detecting BAV; however, we must remember it is semi-invasive and it also has some limitations in order to assess the upper part of the ascending aorta and the proximal arch. The BAV phenotypic expression represents an anatomic continuum of increasing non-fused cusp commissural angles and increasing similarity of cusp size and shape. This spectrum goes from the partial-fusion BAV (very near to a tricuspid aortic valve) to other phenotypes such us those asymmetric fused, symmetric fused phenotypes with and without a raphe, and finally to the two-sinus BAV, which is considered the most severe defect and is anatomically close to perfect “bicuspidity” [19]. The best view of the phenotype BAV is the TTE parasternal short-axis or its equivalent in TEE, CT, or CMR (Figure 1). The most common type of BAV is the fused one (90–95% of the cases) [19]. This is described as two of the three cusps appearing fused within three aortic sinuses, resulting in two functional cusps commonly different in shape and size. A congenital fibrous ridge is often described between the fused cusps, and it is what we know as “raphe”. The most frequent BAV phenotype is the one with right−left (R−L) fusion, considered to be present in 75% of the cohort. This is followed by the right−non-coronary (R−N) fusion (20–25%), and finally the left−non (L−N) fusion (<3%). The two-sinus BAV type is uncommon and accounts for approximately 5–7% of cases. In contrast to the fused type, the two-sinus BAV appearance suggests that two roughly equal size-shape cusps, each cusp occupying 180 degrees of the annular circumference, are “formed” within only two aortic sinuses, resulting in a two-sinus/two-cusp valve [20] with a latero−lateral (side-to-side) or antero−posterior (front-and-back) position. The presence of an incomplete fusion of two J. Clin. Med. 2022, 11, 456 3 of 16 leaflets1.(mini-raphe) Figure Most frequentcannot beBAV types of easily byvisualized by TTE TTE. (A) BAV [21]raphe without (Figure type2).antero−posterior; In these cases, we (B) J. Clin. Med. 2022, 11, x FOR PEER REVIEW 3 of 17 shouldfusion RC−LC use other with techniques such raphe (arrow); (C)as TEE and RC−NC CT.with fusion Thisraphe mini-raphe (arrow). has been considered to be involved in aorta dilation [22]. The most common type of BAV is the fused one (90–95% of the cases) [19]. This is described as two of the three cusps appearing fused within three aortic sinuses, resulting in two functional cusps commonly different in shape and size. A congenital fibrous ridge is often described between the fused cusps, and it is what we know as “raphe”. The most frequent BAV phenotype is the one with right−left (R−L) fusion, considered to be present in 75% of the cohort. This is followed by the right−non‐coronary (R−N) fusion (20–25%), and finally the left−non (L−N) fusion (<3%). The two‐sinus BAV type is uncommon and accounts for approximately 5–7% of cases. In contrast to the fused type, the two‐sinus BAV appearance suggests that two roughly equal size‐shape cusps, each cusp occupying 180 degrees of the annular circumference, are “formed” within only two aortic sinuses, resulting in a two‐sinus/two‐cusp valve [20] with a latero−lateral (side‐to‐side) or antero−posterior (front‐and‐back) position. The presence of an incomplete fusion of two leaflets (mini‐raphe) cannot be easily visualized by TTE [21] (Figure 2). In these cases, we should Figure 1.use other Most techniques frequent such types of BAVasby TEE and TTE. (A)CT. BAVThis mini‐raphe without has been raphe type considered(B) antero−posterior; Figure 1. Most frequent types of BAV by TTE. (A) BAV without raphe type antero−posterior; to RC−LC be fusionin involved with raphe aorta (arrow); dilation (C) RC−NC fusion with raphe (arrow). [22]. (B) RC−LC fusion with raphe (arrow); (C) RC−NC fusion with raphe (arrow). The most common type of BAV is the fused one (90–95% of the cases) [19]. This is described as two of the three cusps appearing fused within three aortic sinuses, resulting in two functional cusps commonly different in shape and size. A congenital fibrous ridge is often described between the fused cusps, and it is what we know as “raphe”. The most frequent BAV phenotype is the one with right−left (R−L) fusion, considered to be present in 75% of the cohort. This is followed by the right−non‐coronary (R−N) fusion (20–25%), and finally the left−non (L−N) fusion (<3%). The two‐sinus BAV type is uncommon and accounts for approximately 5–7% of cases. In contrast to the fused type, the two‐sinus BAV appearance suggests that two roughly equal size‐shape cusps, each cusp occupying 180 degrees of the annular circumference, are “formed” within only two aortic sinuses, resulting in a two‐sinus/two‐cusp valve [20] with a latero−lateral (side‐to‐side) or antero−posterior (front‐and‐back) position. The presence of an incomplete fusion of two leaflets (mini‐raphe) cannot be easily visualized by TTE [21] (Figure 2). In these cases, we should use other techniques such as TEE and CT. This mini‐raphe has been considered to Figure 2. BAV be involvedBAVinwith partial aorta fusion dilation (forma frustre). Arrows [22]. Arrows show show the the mini mini raphe raphe by by CT CT (A) (A) and and by by TEE TEE (B). (B). In order to solve the limitations limitations ofof the the TTE, TTE, CMR CMR andand CT CT are very useful useful in the morphologic morphologic valve valve evaluation evaluation when when itit is is heavily heavily calcified, calcified, and and can can readily assess aorta diameters [23]. [23].CTCTcan can quantify quantify the the valve valve calcification, calcification, whichwhich canclinicians can help help clinicians to to evaluate valve stenosis evaluate valve severity. The multiplanar stenosis severity. reconstructions The multiplanar permit CMR reconstructions andCMR permit CT toand precisely CT to assess the assess precisely aortic diameters the aortic[24,25]. Although diameters CT Although [24,25]. offers a higher spatial aresolution, CT offers CMR higher spatial provides information resolution, of the information CMR provides valvular dysfunction and left dysfunction of the valvular ventricular function. and leftCine images ventricular (SSFP sequences) function. can be Cine images used (SSFP for measuring sequences) can bethe luminogram used of the for measuring aorta, the particularly luminogram in of the the aortic root, owing the valvular plane movement. Aorta diameters should be measured in double oblique technique) [26] (Figure 3). Screening for coarctation should be performed in BAV patients, however CMR on the first echo is the preferred technique in younger patients in order to avoid radiation. Figure 2. BAV with partial fusion (forma frustre). Arrows show the mini raphe by CT (A) and by TEE (B). In order to solve the limitations of the TTE, CMR and CT are very useful in the morphologic valve evaluation when it is heavily calcified, and can readily assess aorta diameters [23]. CT can quantify the valve calcification, which can help clinicians to evaluate valve stenosis severity. The multiplanar reconstructions permit CMR and CT to precisely assess the aortic diameters [24,25]. Although CT offers a higher spatial resolution, CMR provides information of the valvular dysfunction and left ventricular function. Cine images (SSFP sequences) can be used for measuring the luminogram of the J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4 of 17 aorta, particularly in the aortic root, owing the valvular plane movement. Aorta diameters should be measured in double oblique technique) [26] (Figure 3). Screening for coarctation J. Clin. Med. 2022, 11, 456 4 of 16 should be performed in BAV patients, however CMR on the first echo is the preferred technique in younger patients in order to avoid radiation. Figure Figure 3. 3. BAV BAV by by CT CT showing showing left−right left−rightfusion fusion with with raphe raphe calcification calcification and and mild mild non‐coronary non-coronary sigmoid sigmoid edge calcification (A); CMR showing two-sinus anteroposterior BAV (B); double obliquity edge calcification (A); CMR showing two‐sinus anteroposterior BAV (B); double obliquity image image for for measuring measuring the the maximum maximumdiameter diameterofofthe the aortic aortic root root by by CT CT (C); (C); thoracic thoracic aorta aorta diameters diameters by angio‐CMR sagittal projection; the right upper part shows the aortic root section obtained with by angio-CMR sagittal projection; the right upper part shows the aortic root section obtained with double obliquity image (D). double obliquity image (D). 3. 3. Familial Familial Screening Screening BAV BAV isis diagnosed diagnosed in in 4.6–11% 4.6–11% of of first‐degree first-degree relatives relatives (FDR) (FDR) [27–30]. [27–30]. Moreover, Moreover, the the frequency frequency ofof aorta aorta dilation dilation in in FDR FDR isis nearly nearly 10%10% in in those those with with tricuspid tricuspid aortic aortic valves. valves. In In aa recent recent publication publication byby our our group, group, wewereported reportedthe thepresence presenceofofa amini-raphe mini‐raphebyby CTCTinin 41%41%of of cases with aorta dilation in FDR and an apparent absence of BAV cases with aorta dilation in FDR and an apparent absence of BAV by TTE [31], and further by TTE [31], and further studies studies demonstrate demonstrate that, compared that, compared with BAV with andBAV and tricuspid tricuspid valve patients, valve patients, the the presence presence of a mini‐raphe of a mini-raphe is associated is associated with ascending with ascending aorta flowaorta patternflowalterations pattern alterations with with increased increased flow eccentricity flow eccentricity and increased andvorticity increased [22].vorticity [22].are These data These data in favor of are the in favor ofin the screening the screening FDR of BAV in the FDR of BAV patients. patients. 4. Valvular 4. Valvular Dysfunction Dysfunction In adult In adult patients patientswith withBAV, BAV, the the most most frequent frequent complication complication is is valvular valvular dysfunction, dysfunction, commonly known commonly known asasaortic stenosis aortic (AS), stenosis which (AS), necessitates which surgical necessitates aortic valve surgical aorticreplace- valve replacement (AVR) or repair [3,32,33]. TTE is the technique of choice in the diagnosisquan- ment (AVR) or repair [3,32,33]. TTE is the technique of choice in the diagnosis and and tification of aortic quantification valve valve of aortic dysfunction. The subtype dysfunction. with a with The subtype loweraprevalence of valvular lower prevalence of dysfunction valvular is pure BAV dysfunction without is pure BAV raphe. Thisraphe. without subgroupThisshowed subgroupbothshowed a lower both prevalence a lowerof AS, as well as of aortic regurgitation (AR), in a large international registry prevalence of AS, as well as of aortic regurgitation (AR), in a large international registry that included 2118included that patients 2118 [34]. patients If we differentiate in terms of age, [34]. If we differentiate AR has in terms been of age, AR described has beento be more described frequent in young individuals, and AS more frequent in the older ones to be more frequent in young individuals, and AS more frequent in the older ones [35]. [35]. 4.1. Valve Calcification BAV calcification has been associated with inflammatory processes mediated by hemo- dynamic, molecular, and genetic factors [36]. Calcification is usually localized in the raphe, and it is considered to be a risk factor for developing valve degeneration and aortic stenosis (AS). Stenotic calcification of a BAV could appear more than ten years earlier than in those 4.1. Valve Calcification BAV calcification has been associated with inflammatory processes mediated by hemodynamic, molecular, and genetic factors [36]. Calcification is usually localized in the J. Clin. Med. 2022, 11, 456 raphe, and it is considered to be a risk factor for developing valve degeneration and 5aortic of 16 stenosis (AS). Stenotic calcification of a BAV could appear more than ten years earlier than in those with the tricuspid aortic valve. It is related to conventional cardiovascular risk with the An factors. echocardiographic tricuspid aortic valve. semiquantitative score for aortic It is related to conventional valve calcification cardiovascular has risk factors. been validated [37]. CT calcium scoring is useful for valve stenosis quantification An echocardiographic semiquantitative score for aortic valve calcification has been vali- in doubtful cases. In a large crossectional study of 852 BAV [35] patients, we found dated [37]. CT calcium scoring is useful for valve stenosis quantification in doubtful cases. age, arterial In a largehypertension, dyslipidemia, crossectional study of 852 BAVsmoking, andwe [35] patients, the BAV‐RN found morphotype age, arterial to be hypertension, associated with dyslipidemia, aortic valve smoking, calcification. and the However, CT BAV-RN morphotype score to be was notwith associated associated with aortic valve valve phenotype calcification. [38]. CT score was not associated with valve phenotype [38]. However, 4.2. 4.2. Aortic AorticStenosis Stenosis Adults Adults diagnosed diagnosed with with BAV BAV have have aaclear clearincreased increased risk risk of ofdeveloping developing AS, AS, usually usually secondary secondary to to leaflet leaflet calcification. calcification. Previous studies have showedshowed thatthat over over 1515 years years of of follow follow up, up, 12.3% ofof the thecohort cohortrequired requiredaortic aorticvalve valvereplacement replacement forfor severe severe ASAS [32]. [32]. In In our our daily daily practice, practice, TTETTE is is thethe mostused most usedtechnique techniqueforfor evaluating evaluating thethe presence of of this this complication, complication, and for guiding appropriate management. AS quantification is based on on guiding appropriate management. AS quantification is based the the samesame parameters parameters of tricuspid of tricuspid valves valves (Figure (Figure 4). must 4). We We must remember remember thataortic that the the aortic valve valve area may area may be significantly be significantly underestimated underestimated byby TTEowing TTE owingtotounderestimation underestimation of of aortic aortic annulus annulusmeasurement. measurement.However, However,the theuse useof ofCTA CTAmaymaycorrect correctthese theseunderestimations underestimations[1]. [1]. Figure4.4.Severe Figure Severeaortic aorticstenosis stenosisininBAV BAVwith withsevere severecalcification calcification(arrows) (arrows)(A); (A);the themean meangradient gradientby by continuous‐wave Doppler is 48 mmHg continuous-wave Doppler is 48 mmHg (B). (B). Althoughininsome Although somestudies studies it has it has beenbeen suggested suggested thatthat AS progresses AS progresses fasterfaster in BAVin than BAV than in thein the tricuspid tricuspid aorticaortic valvevalve [39], a[39], a recent recent large large studystudy by Michelena by Michelena et al. et al.showed [40] [40] showed that that BAV BAV and tricuspid and tricuspid aorticaortic valvevalve stenosis stenosis havehave similar similar progression progression rates, rates, withwith evidence evidence of of accelerated accelerated progression progression (non‐linearity) (non-linearity) in those in those attaining attaining severesevere AS. Determinants AS. Determinants of rapidof rapid progression progression in BAV-AS,in again, BAV‐AS, again, arecardiovascular are modifiable modifiable cardiovascular risk factors, risk factors, particularly for particularly patients withfor BAV patients who are with <60BAV years who are <60 years of age. of age. 4.3. 4.3. Aortic AorticRegurgitation Regurgitation Valvular Valvulardysfunction dysfunctionasas ARAR is more frequent is more frequentin younger patients, in younger but also patients, in males but also [41]. in males Although its prevalence ranges between 47% and 64%, moderate [41]. Although its prevalence ranges between 47% and 64%, moderate−severe grade− severe grade appears in less than 30% of individuals [9,32–35,42]. Annular dilation and cusp prolapse appears in less than 30% of individuals [9,32–35,42]. Annular dilation and cusp prolapse or retraction isorthe most common retraction underlying is the most commoncause of chronic underlying causeregurgitation, acting eitheracting of chronic regurgitation, alone either or in combination [43]. The evaluation alone or in combination [43]. The of AR severity evaluation in BAV of AR by TTE severity is challenging, in BAV given that by TTE is challenging, eccentric given that eccentric jets are common. In some cases, CMR may be superior to TTEAR jets are common. In some cases, CMR may be superior to TTE for quantifying for (Figure 5) [44,45]. quantifying The CMR AR (Figure phase contrast 5) [44,45]. The CMR is accurate and reproducible phase contrast is accuratein ARreproducible and assessment with in ARthe estimation assessment of the with regurgitantofvolume the estimation and regurgitant the regurgitant volume andfraction. We labelled regurgitant a fraction. regurgitant fraction of more than 30% as severe [46]. We labelled a regurgitant fraction of more than 30% as severe [46]. J. J. Clin. x FOR PEER REVIEW Clin. Med. 2022, 11, 456 66 of 17 of 16 Figure 5. Figure 5. Severe Severeaortic aorticregurgitation regurgitation in ainBAV. a BAV. (A) Eccentric (A) Eccentric jet in parasternal jet in parasternal long axis‐view long axis-view (arrow). (arrow). (B) The short‐axis view shows the elliptic shape of the regurgitant (B) The short-axis view shows the elliptic shape of the regurgitant orifice (arrows) orifice (arrows) in the in the aortic aortic annulus (circle). Ao—aorta; LV—left ventricle. annulus (circle). Ao—aorta; LV—left ventricle. 5. Aorta Involvement Ascending aorta Ascending aortadilation dilation hashas been been frequently frequently described described in patients in patients with BAV. with BAV. Previous Previoushave studies studies shown have shown it to it to be be present inpresent in 56% ofunder 56% of patients patientsthe under age of the age up 30, but of 30, but to 88% upthose in to 88% in those over over 30 [32,33,42]. 30 [32,33,42]. In daily practice, In daily practice, TTE is the TTE is the most most used used technique technique to to assess assess the the dilatation dilatation of the proximal of the proximal ascending ascending aorta. Although aorta. Although the aorticthe rootaortic root and and proximal ascending aorta are well proximal ascending visualized aorta are wellinvisualized the left parasternal in the leftlong-axis parasternalview,long‐axis the mid ascending view, the aorta should be aorta mid ascending visualized should bybe moving the transducer visualized by movingposition to an upper the transducer intercostal position space. to an upper Ascending intercostal aorta space.diameter Ascending by TTEaortausing leading–leading diameter by TTE using edges yield comparable leading–leading values edges to yield inner–inner comparable values edges by CT and CMR to inner–inner [47]. by edges However, CT and CMR failure[47]. to obtain the largest However, failure diameter to obtain by theTTE can diameter largest lead to anby underestimation TTE can lead to ofan theunderestimation aortic root diameter. of the This drawback aortic may be root diameter. important in the presence of root asymmetry ( ≥ 5 mm This drawback may be important in the presence of root asymmetry (≥5 mm betweenbetween cusp-to-cusp diameters), which is described cusp‐to‐cusp in more diameters), thanis50% which of BAV in described patients without more than 50%rapheof BAV and in >40% patients of the without BAV-RN raphe and morphotype in >40% of[48]. theTherefore, BAV‐RN BAV-RN morphotype and cases [48]. without Therefore, raphe may particularly BAV‐RN and cases benefit withoutfrom raphe a CMR/CT study tobenefit may particularly ensure from the true largest aortic a CMR/CT studyroot diameter to ensure the(Figure 3B). true largest Dilation of the mid aortic root diameter (Figure 3B) ascending segment with normal or mild aortic root dilation is observed in 70–80% of patients, and predominant dilation of the Dilation of the mid ascending segment with normal or mild aortic root dilation is aortic root is observed in 20–30% observed[48]. BAV-RN in 70–80% ofmorphotype patients, andspares aortic root predominant dilation dilation andaortic of the shows distal root ascending is observed in of the aorta, while BAV-LR more commonly dilates the aortic 20–30% [48]. BAV‐RN morphotype spares aortic root dilation and shows distal ascending root and spares the arch [35]. AR is independently of the aorta, while BAV‐LR associated morewith aortic rootdilates commonly dilation the[49]. aortic root and spares the arch Table 1 shows a comparison of the imaging [35]. AR is independently associated with aortic root dilation [49]. modalities for diagnostic features of bicuspid aortic valve. In Figure 6, the role of multimodality Table 1 shows a comparison of the imaging modalities for diagnostic imaging for the features diagnosticof features in bicuspid valve is specified. bicuspid aortic valve. In Figure 6, the role of multimodality imaging for the diagnostic features in bicuspid valve is specified. Table 1. Comparison of imaging modalities for diagnostic features of bicuspid aortic valve. TTE— transthoracic echocardiography; CT—computed tomography. TTE CT MRI J. Clin. Med. 2022, 11, 456 7 of 16 VALVE MORPHOTYPE +++ ++ +++ RAPHE +++ +++ ++ Table 1. Comparison of imaging modalities for diagnostic features of bicuspid aortic valve. TTE— transthoracic echocardiography; VALVE DEGENERATION CT—computed tomography. ++ +++ ++ AORTIC STENOSIS TTE ++ CT ++ MRI+ VALVE MORPHOTYPE +++ ++ +++ AORTIC REGURGITATION RAPHE +++ ++ +++ ‐ +++++ VALVE DEGENERATION ++ +++ ++ AORTIC ROOT DILATION + +++ +++ AORTIC STENOSIS ++ ++ + AORTIC REGURGITATION ++ - +++ TUBULAR SEGMENT DILATION + ++ +++ AORTIC ROOT DILATION + +++ +++ TUBULAR AORTICSEGMENT DILATION COARCTATION + + ++ +++ ++++++ AORTIC COARCTATION + +++ +++ MRI—magnetic resonance MRI—magnetic resonance imaging. imaging. ++++++ = very = very positive; positive; ++ = positive; ++ = positive; + -==fair; + = fair; no. ‐ = no. Figure 6. Figure Multimodalityimaging 6. Multimodality imagingforfor diagnostic diagnosticandand follow‐up follow-upofof features features in in bicuspid bicuspid aortic aortic valve valve patients. **Follow‐up patients. Follow-updepending depending on on the the severity severity of of valvular valvular dysfunction dysfunction and and aorta aorta dilation. dilation. ** **When When disparity between TTE disparity TTE and andCT/MRI, CT/MRI, >3>3 mmmmfollow-up follow‐upshould shouldbebeperformed performed annually annually byby TTE TTE andand ev- every 3 years ery 3 years byby CT/MRI CT/MRI if the if the maximum maximum diameter diameter is <45 is <45 mm, mm, every every 2 years 2 years if it if is it is between between 45–50 45–50 mm, mm, and yearly and yearly if >50 if mm.>50Abbreviatures: mm. Abbreviatures: TTE: transthoracic TTE: transthoracic echocardiography, echocardiography, MRI: magnetic MRI: resonance magnetic resonance imaging; CT—computed tomography; Fusion L‐R—left‐right imaging; CT—computed tomography; Fusion L-R—left-right sigmoids fusion; R−NC—right sigmoids fusion; R−NC—−non right−non coronary sigmoids; L−NC— left‐non coronary sigmoids. AS—aortic stenosis; AR—aortic coronary sigmoids; L−NC— left-non coronary sigmoids. AS—aortic stenosis; AR—aortic regurgita- regurgitation. tion. 6. 6. Imaging ImagingPredictors Predictors Very Very fewfewstudies studieshave have assessed assessed the the progression progression of valvular of valvular dysfunction dysfunction and and ascend- ascending aorta dilation ing aorta dilation in BAVinpatients. BAV patients. Data regarding Data regarding the association the association between between BAV BAV leaflet leaflet morphology morphology and AS and areAS are conflicting. conflicting. BeppuBeppu et al. et [50]al.reported [50] reported that BAV‐LR that BAV-LR was was more more likelylikely associated associated withrapid with the the rapid development development of AS.ofNevertheless, AS. Nevertheless, in a larger in a larger study,study, Kong et al. [34] Kong et al.reported that BAV-RN [34] reported that BAV‐RN and BAV-LN havehave and BAV‐LN a higher incidence a higher of significant incidence AS. of significant The population-based longitudinal study by Michelena et al. [51] failed to identify AS. The population‐based longitudinal study by Michelena et al. [51] failed to identify any any rela- tionship between relationship BAV morphotypes between BAV morphotypes and AS upon and follow-up. AS upon Regarding follow‐up.theRegarding progressiontheof AR, the only of progression variables AR, thewere onlymales, arterial variables hypertension, were and sigmoid males, arterial prolapse hypertension, andreported sigmoidin transverse prolapse studies in reported [35,52]. transverse studies [35,52]. Multiple studies [53] have demonstrated that the segment that presents the maximum growth rate is the tubular ascending aorta (0.4 to 0.6 mm per year). This rate is influenced by age, baseline aorta diameter, associated valve dysfunction (regurgitation vs. stenosis), and location of the dilation (ascending versus root) [54,55]. Accumulated evidence shows that the root phenotype might represent a more severe form of aortopathy, possibly related to a genetic underlying condition that could contribute to the pathogenesis, especially Multiple studies [53] have demonstrated that the segment that presents the maximum growth rate is the tubular ascending aorta (0.4 to 0.6 mm per year). This rate is influenced by age, baseline aorta diameter, associated valve dysfunction (regurgitation J. Clin. Med. 2022, 11, 456 8 of 16 vs. stenosis), and location of the dilation (ascending versus root) [54,55]. Accumulated evidence shows that the root phenotype might represent a more severe form of aortopathy, possibly related to a genetic underlying condition that could contribute to the ifpathogenesis, compared with the ascending especially phenotype. if compared Furthermore, with the ascending this root phenotype phenotype. has been Furthermore, this described to be associated with aortic events in the postoperative period of those who root phenotype has been described to be associated with aortic events in the postoperativehad undergone simple period of those whoaortic hadvalve replacement undergone simple(Figure 7). replacement (Figure 7). aortic valve Figure7.7. (A) Figure (A) BAV BAVRC RC−LC sigmoid fusion −LC sigmoid fusion in in aa patient patient with with Marfan Marfan syndrome. syndrome. (B) (B) Severe Severe aortic aorticroot root dilation and severe aortic regurgitation (arrow). Ao—aortic root; LV— left ventricle. dilation and severe aortic regurgitation (arrow). Ao—aortic root; LV— left ventricle. 6.1. 6.1. Aorta Aorta Biomechanics Biomechanics Predictor PredictorParameters Parameters In Inorder orderto to non-invasively evaluate non‐invasively thoracic evaluate aorta stiffness, thoracic we can we aorta stiffness, measure can distensi- measure bility, but also the pulse wave velocity of the propagation of flow distensibility, but also the pulse wave velocity of the propagation of flow by CMR.by CMR. Aorta Aorta distensibility assesses the distensibility assesses therelative relativechangechangeinin the the cross-sectional cross‐sectional areaarea during during the the cardiac cycle divided by the local pulse pressure. Aorta distensibility is most often cardiac cycle divided by the local pulse pressure. Aorta distensibility is most often assessed assessed inin the the ascending ascending aorta aorta and and less-often less‐often in in the the aortic aortic root, root, owing owing toto the the difficulty difficulty generated generatedby byits itsmotion motionand andnon-circular non‐circulararea area[56]. [56]. Ascending Ascendingaorta aorta distensibility distensibilityhashasbeen been found to be lower in predominantly-dilated BAV patient groups compared found to be lower in predominantly‐dilated BAV patient groups compared to the healthy to the healthy population population[56–59]. [56–59]. Pulse Pulsewave wavevelocity velocity(PWV) (PWV)depends dependsmainly mainlyon onwall wallstiffness stiffnessandandlocal localdiameter: diameter:the the stiffer stiffer and/or smaller an artery is, the faster waves propagate in it. PWV showed the and/or smaller an artery is, the faster waves propagate in it. PWV showed the best best association associationwith with ascending ascending aorta aorta dilation dilation in in BAV BAV patients, patients, beyond beyond the the clinical clinical risk risk factors. factors. The The most significant advantages of PWV are that, unlike aortic distensibility, it does not most significant advantages of PWV are that, unlike aortic distensibility, it does not rely relyononany anygeometric geometricassumptions assumptions andandit isit not based is not on local based pressure. on local A recent pressure. studystudy A recent [56] reported regional [56] reported PWVPWV regional by 4D-flow CMRCMR by 4D‐flow in BAV patients. in BAV Non-dilated patients. Non‐dilatedBAV BAV patients had patients a similar PWV to healthy controls in both the ascending and descending aorta, whereas had a similar PWV to healthy controls in both the ascending and descending aorta, dilated BAV patients did not differ from dilated tricuspid valve patients. Furthermore, whereas dilated BAV patients did not differ from dilated tricuspid valve patients. the relationship between PWV and tubular aorta dilation was biphasic: first it decreased Furthermore, the relationship between PWV and tubular aorta dilation was biphasic: first and then it increased throughout dilation with a clear turning point at 50mm, which may it decreased and then it increased throughout dilation with a clear turning point at 50mm, highlight the end of aortic adaptation to dilation severity [56]. which may highlight the end of aortic adaptation to dilation severity [56]. 6.2. Aortic Flow Hemodynamic Parameters 6.2. Aortic Flow Hemodynamic Parameters 4D-flowCMR is very useful in the evaluation of abnormal ascending aorta flow in BAV 4D‐flowCMR patients is very studies (Figure 8). Several useful in the shown have evaluation of abnormal the flow ascending in the aorta aorta flow of BAV patients in to be BAV patients (Figure 8). Several studies have shown the flow in the aorta of BAV patients eccentric, not directed in the same direction of the aorta [60–63]. Such flow abnormalities, to be also eccentric, reported not directed in non-dilated in the aortas, aresame direction thought of the to produce aorta in changes [60–63]. Suchstress wall shear flow abnormalities, also reported in non‐dilated aortas, are thought to produce changes (WSS), the force per unit of area exerted tangentially by blood on the aortic wall, which in wall is shear stress (WSS), the force per unit of area exerted tangentially by blood on the associated with elastic fiber degeneration and extracellular matrix dysregulation [64]. The aortic 4D-flow MRI shows different local flow abnormalities associated with the different leaflet fusion patterns [60] in particular, unlike at the ascending tract, where average systolic wall shear stress with BAV-RL and BAV-RN reached similar magnitudes. Higher shear stress values were found at the more proximal tract of the aorta with BAV-RL. However, the RN morphotype spared dilation at the root level and showed higher in-plane shear stress in wall, which is associated with elastic fiber degeneration and extracellular matrix dysregulation [64]. The 4D‐flow MRI shows different local flow abnormalities associated with the different leaflet fusion patterns [60] in particular, unlike at the ascending tract, where average systolic wall shear stress with BAV‐RL and BAV‐RN reached similar J. Clin. Med. 2022, 11, 456 9 of 16 magnitudes. Higher shear stress values were found at the more proximal tract of the aorta with BAV‐RL. However, the RN morphotype spared dilation at the root level and showed higher in‐plane shear stress in cross sections at the tubular distal level. Interestingly, cross sections partial at theleaflet aortic valve tubular distalalevel. fusion, formeInterestingly, partial fruste BAV, may aortic alter valve aortic flowleaflet fusion, patterns and amay forme fruste lead BAV, dilation to aorta may alter[22,65]. aortic flow In a patterns and may longitudinal study,lead ourtogroup aorta dilation proved [22,65]. that in In a longitudinal patients with BAV study, our group without proved significant that indysfunction, valvular patients withcircumferential BAV without significant wall shear valvular stress component independently predicted progressive dilationindependently dysfunction, circumferential wall shear stress component predicted of the ascending aorta. progressive dilation of the ascending aorta. Notably, mapping of WSS further Notably, mapping of WSS further allowed for establishing ascending aorta regions with allowed for establishing ascending aorta the fastest dilation rates [66].regions with the fastest dilation rates [66]. Figure8.8.(A) Figure (A)Thoracic Thoracicaorta aortaby byCMR CMRimages imagesofofBAV BAVwith withRCRC−LC fusion;(B) −LC fusion; (B)4D-MRI 4D‐MRIdimensional dimensional flow. Note that flow impinges on the outer curvature of the proximal ascending aorta (arrows), flow. Note that flow impinges on the outer curvature of the proximal ascending aorta (arrows), including the root (red arrow). including the root (red arrow). 7.7. Imaging ImagingSurveillance Surveillance In Inclinical clinicalpractice, practice,the themodality modalityused usedfor forthe theserial serial evaluation evaluationof of valvular valvulardysfunction dysfunction isisTTE, TTE,as aswell wellasasfor forthe themeasurement measurementof ofmaximum maximumdiameters, diameters,thus thushelping helpingto todetermine determine the the timing timing of ofelective elective surgery. surgery. Follow-up Follow‐up by by imaging imaging test test isis different different depending depending on on the the baseline valvular dysfunction severity. In mild abnormalities, a baseline valvular dysfunction severity. In mild abnormalities, a control every 3–5 years control every 3–5 years may maybe beenough, enough,while whileaa6–12 6–12month monthinterval intervalisismore moreadvisable advisablein insevere severecases. cases.InInpatients patients with withrootrootor ortubular tubularascending ascendingaorta aortadiameter diameter>40 >40mm, mm,CT CTor orCMRCMRshould shouldbe beperformed performed to toevaluate evaluatethe thecorrelation correlationwithwiththe theecho echomeasurements. measurements.IfIfmeasurements measurementsare arecomparable comparable among amongtechniques, techniques,then thenfuture futureinterval intervalmeasurements measurementscan canbebeobtained obtainedby byTTE TTEwith withrepeat repeat CT or CMR every 3–5 years. If the initial measurements are discrepant CT or CMR every 3–5 years. If the initial measurements are discrepant (>3 mm), CT (>3 mm), CT or CMR or should be the technique of choice. In more advanced aorta CMR should be the technique of choice. In more advanced aorta dilation (>50 mm), dilation (>50 mm), imaging control imaging should controlbeshould performed at least yearly. be performed Measurements at least should be should yearly. Measurements taken with the same be taken with imaging modality and technique (i.e., ECG-gated) and be compared the same imaging modality and technique (i.e., ECG‐gated) and be compared side‐by‐side side-by-side by an experienced by an experienced reader.reader. The tubular The tubularascending aorticaortic ascending growth rate rate growth waswasrecently reported recently reportedto range from 0.4 to 0.6 mm/year [67]. Although these represent “artificial-annualized” to range from 0.4 to 0.6 mm/year [67]. Although these represent “artificial‐annualized” rates, itrates, remains unlikelyunlikely it remains that patients will dilate that patients at more will dilatethan 3 mm/year. at more than 3 It is also important mm/year. It is also to important to note that a diameter change of 2 mm is within the margin ofcurrent note that a diameter change of 2 mm is within the margin of error by error by imaging current modalities [68]. Therefore, an interval dilation of ≥3 mm should be considered clinically significant. Recently, a semi-automatic technique to map aortic dilation rate from pairs of CTs was presented and validated, allowing for a reliable assessment of the growth rate from a much shorter follow-up duration [68]. J. Clin. Med. 2022, 11, 456 10 of 16 8. Complications: Surgical and TAVI Indications The most common complications in patients with BAV are aortic valve replacement, which occurs in over 50% of patients, followed by ascending aortic aneurysm formation, occurring in over 25%. In the population-study reported by Michelena et al. [51], the incidence in 20 years of follow-up of aortic valve replacement was 25 ± 4% (70% of them due aortic stenosis). In the same series, the incidence of ascending aorta replacement was 5 ± 2% and surgery for aortic coarctation was 4 ± 1%. Coarctation of the aorta is present in 7–10% of adults with BAV, whereas BAV is present in 50–60% of patients with coarcta- tion. Concomitant coarctation is associated with a higher risk of aortic complications [25]. The least frequent, but most deadly, complications are infective endocarditis and aortic dissection. 8.1. Infective Endocarditis Infective endocarditis is a severe complication in BAV patients with an incidence of 9.9 (95% CI, 4.4–22) per 10,000 patient-years, resulting in an age-adjusted relative risk of IE for those with native BAVs of 16.9 (95% CI, 7.6–37.6) compared with the general Olmsted County population (p < 0.0001) [4]. Prompt diagnosis should be made to improve prognosis, as in BAV, infective endocarditis incur a greater severity of complications, like a higher risk for the formation of abscesses. The echocardiogram remains the gold standard technique to rule out the presence of infective endocarditis. The sensitivity of TTE for the detection of vegetations in a BAV ranges from 50 to 90% [69]. Thus, initial negative images do not definitely dismiss the diagnosis. When clinical suspicion is high, patient should undergo a TEE, which in these cases has a sensitivity of 90–100% [69]. This technique also permits the diagnosis of secondary complications such as abscesses or paravalvular involvement. 8.2. Aortic Dissection The most feared BAV complication is aortic dissection, with a reported incidence of 3.1 cases per 10,000 patient-years, which is eight times that of the general population, increasing to 0.5% in patients with aortic diameters >45 mm. Michelena et al. [70] published a series of 47 BAV patients with aortic dissection and found that the maximum ascend- ing aortic diameter at aortic dissection was higher in patients with BAV (66 ± 15 mm vs. 56 ± 11 mm, p = 0.0004). Furthermore, previous aortic valve replacement was more com- mon in BAV (23% vs. 6%, p = 0.02) and 23% had a history of previous repair coarctation. Although a diagnostic of aortic dissection is feasible by TTE when the intimal flap is visual- ized in the proximal ascending aorta, CT is the technique of choice. TEE plays a crucial role in monitoring surgical treatment in the operating room. 8.3. Aortic Stenosis: Surgical and TAVR Indications Surgical treatment indications of valvular dysfunction are based on TTE information and are similar to the tricuspid aortic valve [71]. In aortic stenosis, intervention is recom- mended in symptomatic patients with severe, high-gradient aortic stenosis with a mean gradient ≥40 mmHg, peak velocity ≥4.0 m/s, and valve area 1.0 cm2 (or ≤ −0.6 cm2 /m2 ). Similarly, in patients with severe low-flow (stroke volume index ≤35 mL/m2 ) low-gradient (<40 mmHg) aortic stenosis with reduced ejection fraction (<50%). In asymptomatic pa- tients, surgery is also indicated with LVEF >55% if the procedural risk is low and one of the following parameters is present: mean gradient ≥ 60 mmHg or maximum velocity > 5 m/s, severe valve calcification and velocity progression ≥ 0.3 m/s/year, or markedly elevated BNP levels without other explanation. Nowadays, TAVR is an established therapy option for patients with symptomatic severe AS. Although the first randomized trials considered BAV as an exclusion criterion, real-life registries have shown that a significant number of patients have already been treated with TAVR [72]. It has been reported that this intervention, when performed in patients suffering from BAV stenosis, is associated with higher rates of paravalvular re- gurgitation, early mortality rates, and a likelihood of conversion to surgery. This poor J. Clin. Med. 2022, 11, 456 11 of 16 prognosis is mainly related to the anatomical characteristics of BAV: more elliptical annulus, enlarged aortic root and ascending aorta, and unequally sized leaflets along with asym- metric leaflet calcification. All of this information is well defined by CT angiography. The recent BAV stenosis TAVR Registry [73] found that outcomes of TAVR in bicuspid aortic stenosis depend on the valve morphology. Calcified raphe and excess leaflet calcification are associated with increased risk of procedural complications and midterm mortality. The design of new-generation devices, and the increasing use of multidetector CT scan to preoperatively size the aortic annulus have contributed to the near disappearance of these fearsome complications. In fact, the international registry on TAVR in BAV stenosis reported no significant paravalvular regurgitation when new generation devices are used [73], as well as lower rates of annulus rupture or conversion to surgery [74]. 8.4. Aortic Regurgitation: Valve Repair and Replacement In aortic regurgitation, aortic valve replacement is recommended in asymptomatic patients with end-systolic diameter by TTE > 50 mm or this diameter indexed by body surface area > 25 mm/m2 , with an ejection fraction ≤ 50%. Valve-preserving surgery and repair of regurgitant BAV have evolved into an increas- ingly used alternative to replacement [75]. TEE plays a critical role in determining the reparability of the regurgitant BAV, which is successful more frequently in BAV than in tricuspid aortic valves [76], with a low cumulative reoperation incidence of 20% at 15 years when combined with root remodeling. Typically, the main mechanism leading to BAV regurgitation is prolapse of the fused cusp (for fused BAV types) [77,78]. Assessment of BAV symmetry for the fused BAV type, defined by the angle between the commissures of the non-fused cusp, is key information in surgical BAV repair for pure aortic regurgi- tation. The orientation of the two true commissures affects post-repair outcomes; when the commissures are located 160◦ to 180◦ apart, leaflet stresses are lower, and 10-year freedom-from-reoperation rates can be more than 40% higher than in patients with less than a 160◦ commissural orientation [79]. Anatomic predictors of possible repair failures have been well identified and solutions have been developed [80]. Using current techniques, most non-calcified BAVs can be preserved or repaired. Excellent repair durability and freedom from valve-related com- plications can be achieved if all pathologic components of aortic valve and root including annular dilation are corrected. Calcifications of the raphe or cusp retraction (geometric height < 20 mm) that cannot be treated by direct approximation of the cusp tissue are better treated by replacement. An unfavorable commissural orientation will increase the complexity of the repair and decrease its durability [75]. Although asymmetric or very asymmetric BAV can be repaired, they represent a higher technical challenge for the surgeon. Using current approaches for the selection of repairable valves and also for repair strategies, the isolated repair of a regurgitant BAV has been possible, with a 10-year freedom from reoperation of 90% [75]. 8.5. Ascending Aorta Surgery The European Society of Cardiology [71] and the American Association for Thoracic Surgery consensus [67] document recommended surgery for aortic dilation exceeding 55 mm in BAV patients similar to the general population. Replacement of the ascending aorta/root should be performed when aorta diameter is ≥50 mm in patients with risk factors (i.e., root phenotype or predominant aortic regurgitation, uncontrolled hypertension, family history of aortic dissection, coarctation, and aorta growth-rate >3 mm/year). In patients who are candidates for surgery based on valve dysfunction, it is recommended to replace the root and/or ascending aorta when the maximum diameter is >45 mm. An indexed aortic diameter cut-off of greater than 2.75 cm/m2 r and an aortic cross- sectional area to height ratio of greater than 10 cm/m2 may be used to guide earlier surgical intervention in patients with small stature; earlier intervention is occasionally justified in patients with a strong preference for early surgery. Finally, surgical repair may be J. Clin. Med. 2022, 11, 456 12 of 16 performed at a lower threshold (i.e., 5.0 cm) if the patient has a low operative risk and the procedure is performed by an experienced operative team with established results. 9. Critical Knowledge Gaps Despite significant advances in understanding BAV disease in the last decade, many important questions remain to be answered. Why one BAV becomes stenotic, another regurgitant, another is associated with aortic dilation, and yet another continues to be func- tional throughout a lifetime, is fundamentally unknown and unpredictable, and remains unresolved. Research should be implemented in order to: (a) individualize the imaging follow-up and establish the multimodality protocol to recommend lifestyle and surgical treatment indication; (b) define the predictors of valve dysfunction, especially aortic valve calcification and aorta dilation; (c) specify whether the indication for surgery should be based on the aorta diameter in its absolute value or indexed by body surface area or by height; (d) confirm that aortic root dilation with associated regurgitation presents a greater risk of aortic dissection and therefore advance the indication for surgery when its diameter is ≥50 mm; and (e) determine which the imaging biomechanical parameter can independently predict the rapid progression of aortic dilation. Considering the high prevalence of BAV and the marked heterogeneity of its evolution, it is important to identify patients with a rapid evolution profile compared to more stable ones. Imaging techniques should provide this information, which would facilitate better personalization of follow-up, lifestyle, possible medical treatment, and better timing in the indication of surgical treatment. 10. Highlights - Multimodality imaging is the cornerstone of the diagnosis, follow-up, and surgical treatment indication in BAV patients. - Although TTE is the technique of choice to identify valve morphotype, valve dysfunc- tion, and ascending aorta dilation, CT and CMR improve the accuracy of aorta size measurement. - A major benefit of CT is its superior spatial resolution, by which the aortic valve can be evaluated for morphology and calcification, ascending aorta size accuracy, and reproducibility measured and coronary arteries assessed. - CMR offers the unique opportunity to transition from anatomic to dynamic imaging of the ascending aorta by assessing its functional properties and blood flow patterns. 4D-flow CMR may provide new parameters to predict the rate of progressive aorta enlargement. - Therefore, a multimodality approach may offer a comprehensive assessment of mor- phology, risk stratification, and therapy guidance of BAV disease. Author Contributions: Conceptualization, A.E.M.; methodology, A.E.M.; software, A.E.M. and A.L.-S.; validation, A.E.M.; formal analysis, A.E.M. and A.L.-S.; investigation, A.E.M. and A.L.-S.; resources, A.E.M.; data curation, A.E.M. and A.L.-S.; writing—original draft preparation, A.E.M. and A.L.-S.; writing—review and editing, A.E.M. and A.L.-S.; visualization, all authors; supervision, A.E.M.; project administration, A.E.M.; funding acquisition, A.E.M. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. J. Clin. Med. 2022, 11, 456 13 of 16 References 1. Michelena, H.I.; Prakash, S.K.; Corte, A.D.; Bissell, M.M.; Anavekar, N.; Mathieu, P.; Bosse, Y.; Limongelli, G.; Bossone, E.; Benson, D.W.; et al. 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