Journal of Cardiovascular Development and Disease

Systematic Review Multimodality Imaging of the Anatomy of the Aortic Root

Vera Lucia Paiocchi 1, Francesco F. Faletra 1,*, Enrico Ferrari 1, Susanne Anna Schlossbauer 1, Laura Anna Leo 1 and Francesco Maisano 2

1 Division of Cardiology, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland; [email protected] (V.L.P.); [email protected] (E.F.); [email protected] (S.A.S.); [email protected] (L.A.L.) 2 Cardiac Surgery, Università Vita Salute San Raffaele, via Olgettina 58, 20132 Milano, Italy; [email protected] * Correspondence: [email protected]; Tel.: +41-91-805-3179; Fax: +41-91-805-3167

Abstract: The aortic root has long been considered an inert unidirectional conduit between the left ventricle and the ascending aorta. In the classical definition, the aortic valve leaflets (similar to what is perceived for the atrioventricular valves) have also been considered inactive structures, and their motion was thought to be entirely passive—just driven by the fluctuations of ventricular–aortic gradients. It was not until the advent of aortic valve–sparing surgery and of transcatheter aortic valve implantation that the interest on the anatomy of the aortic root again took momentum. These new procedures require a systematic and thorough analysis of the fine anatomical details of the components of the so-called aortic valve apparatus. Although holding and dissecting cadaveric heart specimens remains an excellent method to appreciate the complex “three-dimensional” nature of the



 aortic root, nowadays, echocardiography, computed tomography, and cardiac magnetic resonance provide excellent images of cardiac anatomy both in two- and three-dimensional format. Indeed, Citation: Paiocchi, V.L.; Faletra, F.F.; modern imaging techniques depict the aortic root as it is properly situated within the thorax in an Ferrari, E.; Schlossbauer, S.A.; Leo, attitudinally correct cardiac orientation, showing a sort of “dynamic anatomy”, which admirably L.A.; Maisano, F. Multimodality joins structure and function. Finally, they are extensively used before, during, and after percutaneous Imaging of the Anatomy of the Aortic structural heart disease interventions. This review focuses on the anatomy of the aortic root as Root. J. Cardiovasc. Dev. Dis. 2021, 8, revealed by non-invasive imaging techniques. 51. https://doi.org/10.3390/ jcdd8050051 Keywords: aortic root; echocardiography; computed tomography (CT); cardiac magnetic resonance

Academic Editor: Nina (CMR) Ajmone Marsan

Received: 24 March 2021 Accepted: 1 May 2021 1. Introduction Published: 4 May 2021 Cardiac anatomy is usually taught to medical students on the basis of examination of the cadaveric heart specimens. Indeed, holding and dissecting a human heart remains Publisher’s Note: MDPI stays neutral an excellent method to appreciate the complex “three-dimensional” anatomy of the heart. with regard to jurisdictional claims in However, it must be recognized that cardiac anatomy is, “per se”, extremely complex and published maps and institutional affil- not always does it become part of the student’s cultural background, especially when it is iations. learned in the first years of medical school as a small part of the body’s anatomy. In addition, anatomical exploration is done in the flaccid, cadaveric heart. Today, echocardiography, computed tomography (CT), and cardiac magnetic resonance (CMR) provide excellent images of cardiac anatomy both in two- and three-dimensional format. Although these Copyright: © 2021 by the authors. techniques are mainly used to discover pathological features, they also offer exceptional Licensee MDPI, Basel, Switzerland. images of normal cardiac anatomy. For many aspects, these techniques can be considered This article is an open access article nowadays as a kind of novel “anatomical gold standard” for the following reasons: First, distributed under the terms and differently from explanted hearts, these techniques depict the cardiac anatomy as it is conditions of the Creative Commons properly situated within the thorax in an attitudinally correct cardiac orientation. Second, Attribution (CC BY) license (https:// they have the unique ability to show “live” images from the beating heart, a sort of creativecommons.org/licenses/by/ “dynamic anatomy”, which admirably joins structure and function. Third, the rapid 4.0/).

J. Cardiovasc. Dev. Dis. 2021, 8, 51. https://doi.org/10.3390/jcdd8050051 https://www.mdpi.com/journal/jcdd J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 2 of 20 J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 2 of 20 J. Cardiovasc. Dev. Dis. 2021, 8, 51 2 of 18

progression of percutaneous structural heart disease interventions highlights the need to progression of percutaneous structural heart disease interventions highlights the need to revisit cardiac anatomy using a multimodality approach. These non-invasive techniques revisitprogression cardiac ofanatomy percutaneous using a structural multimodality heart diseaseapproach. interventions These non-invasive highlights techniques the need to have reached an optimal agreement with anatomy. Indeed, their accuracy in providing haverevisit reached cardiac an anatomy optimal usingagreement a multimodality with anatomy. approach. Indeed, These their non-invasiveaccuracy in providing techniques fine anatomic details has been verified in several studies by comparing side-by-side ana- finehave anatomic reached details an optimal has been agreement verified with in several anatomy. studies Indeed, by theircomparing accuracy side-by-side in providing ana- fine tomic specimens and non-invasive images [1–9]. This review focuses on the anatomy of tomicanatomic specimens details and has non-invasive been verified images in several [1–9 studies]. This byreview comparing focuses side-by-side on the anatomy anatomic of the aortic root as revealed by non-invasive imaging techniques. thespecimens aortic root and as non-invasiverevealed by non-invasive images [1–9]. imaging This review techniques. focuses on the anatomy of the aortic root as revealed by non-invasive imaging techniques. 2. Aortic Root 2. Aortic Root 2. AorticThe fine Root details of the “aortic root complex” have been often overlooked by the car- The fine details of the “aortic root complex” have been often overlooked by the car- diologyThe community. fine details Two of the main “aortic reasons root complex”explain this have sort been of “disinterestedness” often overlooked by towards the cardi- diology community. Two main reasons explain this sort of “disinterestedness” towards thisology complex community. structure: Two (a) main for reasonsa long time, explain the thisaortic sort root of“disinterestedness” has been considered towards a simple this this complex structure: (a) for a long time, the aortic root has been considered a simple andcomplex inert unidirectional structure: (a) for conduit a long between time, the the aortic left root ventricle has been (LV) considered and the ascending a simple and aorta; inert and inert unidirectional conduit between the left ventricle (LV) and the ascending aorta; (b)unidirectional because aortic conduit leaflets between do not have the left an ventricleextensive (LV) attachment and the ascendingwith the ventricular aorta; (b) because myo- (b) because aortic leaflets do not have an extensive attachment with the ventricular myo- cardium,aortic leaflets their motion do not havewas thought an extensive to be attachment entirely passive—just with the ventricular driven by myocardium, fluctuations their of cardium, their motion was thought to be entirely passive—just driven by fluctuations of LV–AOmotion gradients. was thought The to advent be entirely of aortic passive—just valve–sparing driven bysurgery fluctuations and transcatheter of LV–AO gradients. aortic LV–AO gradients. The advent of aortic valve–sparing surgery and transcatheter aortic valveThe implantation advent of aortic (TAVI) valve–sparing techniques surgery renewed and the transcatheter interest on the aortic anatomy valve of implantation the aortic valve implantation (TAVI) techniques renewed the interest on the anatomy of the aortic root,(TAVI) since techniques both procedures renewed require the interest a systemat on theic anatomy and thorough of the aorticanalysis root, of sincethe fine both ana- pro- root, since both procedures require a systematic and thorough analysis of the fine ana- tomicalcedures details require of the a systematic components and of thorough this valve analysis apparatus of the[10,11]. fine anatomical details of the tomicalcomponents details of of this the valvecomponents apparatus of this [10 ,valve11]. apparatus [10,11]. 3. Terminology 3.3. Terminology Terminology There is a remarkable variability in the terms used to describe the aortic root compo- ThereThere is isa aremarkable remarkable variability variability in in the the te termsrms used used to to describe describe the the aortic aortic root root compo- compo- nents. Table 1 clarifies the terminology for everyday use. nents.nents. Table Table 11 clarifies clarifies the the te terminologyrminology for for everyday everyday use. use. Table 1. Terms used to describe the aortic root components. TableTable 1. Terms 1. Terms used usedto describe to describe the aortic the aortic root rootcomponents. components. Name Meaning NameName Meaning Meaning

The term ventricular–arterialThe term ventricular–arterial junction junction describes describes the border the border between The term ventricular–arterial junction describes the border between the ventricularbetween myocardium the ventricular and myocardium the fibroelastic and the structure fibroelastic of the the ventricular myocardium and the fibroelastic structure of the aortic root.structure Contrary of to the the aortic right root. AV Contrary junction, to where the right the AV pulmonary Ventricular– aortic root. Contrary to the right AV junction, where the pulmonary Ventricular– root is entirelyjunction, supported where the by pulmonary the muscular root isinfundibulum, entirely supported only by the Ventricular–arterialarterial root is entirely supported by the muscular infundibulum, only the arterial left and the right coronary sinuses are partially supported by the junction left and thethe right muscular coronary infundibulum, sinuses are only partially the left and supported the right by the junctionjunction myocardium (see text), being the remaining extent of the aortic root myocardiumcoronary (see text), sinuses being are partiallythe remaining supported extent by of the the aortic root supportedmyocardium by fibrous tissue (see text), (MS being= membranous the remaining septum; extent see of text the and referencessupported [12,13]).by fibrous tissue (MS = membranous septum; see text and referencesaortic [12,13]). root supported by fibrous tissue (MS = membranous septum; see text and references [12,13]).

The term “cusps” refers to the moving parts of the aortic The term “cusps”root. When refers seen to in the closed moving position parts from of the the aortic ventricular root. When The term “cusps” refers to the moving parts of the aortic root. When seen in closedperspective, position this componentfrom the isventricular similar to the perspective, surface of a this seen in closed position from the ventricular perspective, this componentmolar is similar tooth (calledto the cusp).surface The of terma molar is used tooth to describe (called thecusp). component is similar to the surface of a molar tooth (called cusp). The term structureis used ofto the describe valve (i.e., the unicuspidal, structure bicuspid,of the andvalve (i.e., The term is used to describe the structure of the valve (i.e., unicuspidal,tri-cuspid). bicuspid, Literally and tri-cuspid). the term indicates Literally a pointed the term end indicates where unicuspidal, bicuspid, and tri-cuspid). Literally the term indicates Cusps,Cusps, leaflets leaflets a pointed endtwo curveswhere meet.two curves In the meet. aortic root,In the it aortic indicates root, an it intact indicates Cusps, leaflets a pointed end where two curves meet. In the aortic root, it indicates an intact interleafletinterleaflet triangletriangle with with its its apex apex reaching reaching the the sinutubular sinutubular an intact interleaflet triangle with its apex reaching the sinutubular junction. junction. junction. The term leafletThe term means leaflet “small means leaf”, “small which leaf”, describes which describes a thin, a pliable thin, The term leaflet means “small leaf”, which describes a thin, pliable layer. Thispliable term layer.perfectly This fits term the perfectly leaflet fits aspect. the leaflet N= non-coronary, aspect. layer. This term perfectly fits the leaflet aspect. N= non-coronary, L= left coronary,N = non-coronary, R= right coronary L = left coronary,leaflets/cusps. R = right coronary L= left coronary, R= right coronary leaflets/cusps. leaflets/cusps.

J. Cardiovasc. Dev. Dis. 2021, 8, 51 3 of 18 J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 3 of 20 J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 3 of 20 J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 3 of 20 J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 3 of 20

Table 1. Cont.

Name Meaning

In the anatomy of the aortic root this term refers to the most distal Commissures areaIn the where anatomy the insertionsof the aortic of theroot leaflets this term on refersthe aortic to the wall most join distal each Commissures areaIn the where anatomy the insertionsof the aortic of theroot leaflets this term on refersthe aortic to the wall most join distal each other.In the anatomy In the anatomyof the aortic of the root aortic this root term this refers term refers to the to most the most distal Commissures other.area where the insertions of the leaflets on the aortic wall join each CommissuresCommissures other.area where distal the insertions area where of the the insertions leaflets of on the the leaflets aortic on wall the aorticjoin each other. wall join each other.

The aortic annulus is the three-dimensional line that follows the hingeThe aortic line annulusof the leaflets is the three-dimensionalon the aortic wall. line This that line follows of dense the Aortic annulus hingeThe aortic lineThe annulusof aorticthe leaflets annulusis the three-dimensionalon is the the three-dimensional aortic wall. line This linethat line that follows followsof dense the Aortic annulus connectiveThe aortic annulustissue has is thea crown-shaped three-dimensional appearance line that (white follows dotted the connectivehinge linethe oftissue hingethe hasleaflets line ofa thecrown-shaped on leaflets the aortic on the appearance wall. aortic wall.This (white Thisline lineof dotteddense of AorticAortic annulus annulus line).hinge line of the leaflets on the aortic wall. This line of dense Aortic annulus line).connective dense tissue connective has a crown-shaped tissue has a crown-shaped appearance appearance (white dotted line).connective (white tissue dotted has line).a crown-shaped appearance (white dotted line).

This term refers to a circumference that joins the lowest points of theThis leaflet term Thisinsertion.refers term to refersa Although circumference to a circumference neither that anatomically joins that joinsthe lowestor the histologically lowest points of Virtual or theThis leaflet term pointsinsertion.refers ofto the a Although leafletcircumference insertion. neither that Although anatomically joins neitherthe lowestor anatomicallyhistologically points of VirtualVirtual or orrecognizable,This term refers this to terma circumference has become that relevant joins the in lowestthe TAVI points era. of “echocardiogra recognizable,the leaflet orinsertion. histologically this term Although recognizable,has neitherbecome thisanatomically relevant term has in become orthe histologically TAVI relevant era. “echocardiograVirtual“echocardiographic” or Measurementsthe leaflet insertion. of this Although virtual basal neither plane anatomically are used foror histologically the sizing of phic”Virtual annulus or Measurementsrecognizable,in the thisof TAVI this term era. virtual Measurementshas basalbecome plane ofrelevant thisare virtualused in for basalthe the TAVI planesizing era. of “echocardiographic” annulusannulus therecognizable, valve in tricuspid this term valves. has Thisbecome virtual relevant annuls in does the not TAVI have era. an “echocardiogra theMeasurements valve inare tricuspid used of this for the virtualvalves. sizing basalThis of the virtualplane valve are inannuls tricuspidused does for valves. the not sizing have This anof phic” annulus anatomicMeasurements counterpart. of this virtual basal plane are used for the sizing of phic” annulus anatomicthe valve counterpart.virtualin tricuspid annuls valves. does not This have virtual an anatomic annuls counterpart. does not have an anatomicthe valve counterpart.in tricuspid valves. This virtual annuls does not have an anatomic counterpart.

Surgeons fix the prosthetic valves on a circular area lying Surgeons fix the prosthetic valves on a circular area lying between between the nadirs of the sinuses and midway to the theSurgeons nadirs fix of the sinusesprosthetic and valves midway on toa circularthe commissures area lying (the between aortic Surgical theSurgeons nadirs fix commissuresof the sinusesprosthetic (the and aortic valves midway prostheses on toa circularthe have commissures aarea flat sewinglying (the between ring). aortic SurgicalSurgical annulusprosthesesSurgeons fix have the prosthetica flat sewing valves ring). on aThe circular term area“surgical lying annulusbetween” annulus prosthesesthe nadirsThe ofhave the term sinusesa “surgicalflat sewing and annulus midway ring).” refers to The the to termcommissures this “ring “surgical area” (the andannulus aortic” Surgicalannulus refersthe nadirs to this of the “ring sinuses area” and and midway provides to the a precisecommissures reference (the aorticpoint Surgical refersprostheses to thisprovides have “ring a aflat precisearea” sewing and reference providesring). point The a when termprecise the “surgical prosthesisreference annulus is point” annulus whenprostheses the prosthesis have a flat is sutured sewing onring). “supra” The annularterm “surgical position. annulus ” annulus whenrefers theto prosthesisthissutured “ring on is “supra”area” sutured and annular onprovides “supra” position. a annularprecise position.reference point whenrefers theto prosthesisthis “ring isarea” sutured and onprovides “supra” a annular precise position.reference point when the prosthesis is sutured on “supra” annular position.

3.1. The Function of the Aortic Root 3.1.3.1. The The Function Function of ofthe the Aortic Aortic Root Root 3.1. TheTheThe Function aortic aortic root of root the is Aortic isa ahighly highly Root sophisticat sophisticateded and and complex complex apparatus, apparatus, which which has has been been 3.1. TheThe Function aortic root of the is Aortic a highly Root sophisticat ed and complex apparatus, which has been forgedforgedThe by byaortic millions millions root of is of years a years highly of of evolution evolutionsophisticat to to edfunction functionand complex properly properly apparatus, for for a alifetime lifetime which in in hasthe the mostbeen most forged by millions of years of evolution to function properly for a lifetime in the most forgedchallengingchallengingThe by aortic millions physical physical root of environment.is environment.years a highly of evolution sophisticat The The function functions to edfunction ands of of complexthe theproperly aortic aortic apparatus, root rootfor area are lifetime described which in hasthe in Table mostbeen2 . challenging physical environment. The functions of the aortic root are described in Table challenging2.forged PreservingPreserving by millions physical leafletleaflet of integrity integrityenvironment. years of is evolution probably The function theto function most s of relevant relevantthe properly aortic function function root for area lifetimeof ofdescribed the the aortic aorticin the in root. root. Tablemost ItIt 2. Preserving leaflet integrity is probably the most relevant function of the aortic root. It 2.mustchallenging mustPreserving be be said said physical thatleaflet that leaflets leafletsintegrity environment. are are livingis living probably Thestructur structures function thees most subjecteds subjected of relevant the aortic to toa function natural a root natural are biologicalof described biological the aortic turnover. in turnover.root. Table It must be said that leaflets are living structures subjected to a natural biological turnover. mustTheir2.Their Preserving bestructural structural said thatleaflet micro-architecture micro-architectureleaflets integrity are livingis probably isstructur iscontin continuously theuouslyes most subjected relevantrenovated, renovated, to a function natural and and the thebiologicalof micro-injuries the micro-injuries aortic turnover. root. are areIt Their structural micro-architecture is continuously renovated, and the micro-injuries are self-repaired.Theirmust bestructural said thatNevertheless, micro-architecture leaflets are leaflet living integrityis structur contin uouslyesand subjected durability renovated, to aare natural and highly the biological dependentmicro-injuries turnover. on theare self-repaired. Nevertheless, leaflet integrity and durability are highly dependent on the self-repaired.Their structural Nevertheless, micro-architecture leaflet integrityis contin uouslyand durability renovated, are andhighly the dependentmicro-injuries on theare self-repaired. Nevertheless, leaflet integrity and durability are highly dependent on the

J. Cardiovasc. Dev. Dis. 2021, 8, 51 4 of 18

self-repaired. Nevertheless, leaflet integrity and durability are highly dependent on the stress applied to the tissue during the closure and opening phases. The aortic root provides an extraordinary “low-stress environment” that favors leaflet durability [14–16].

Table 2. Functions of the aortic root.

Functions of Aortic Root Allowing the transit of a significant amount of blood with a minimum gradient between the left ventricle and the aorta nsuring a wide flow variation (up to 5 times) Preventing significant back flow, having, at the same time, a robust structural integrity to withstand the aortic pressure Enabling an optimal coronary perfusion Preserving leaflet integrity

3.2. Aortic Root and Surrounding Structures The AO is the cardiac “centerpiece” partially wedged between the atrioventricular orifices. (Figure1A). Viewed from an antero-posterior plane, the aortic root is positioned to the right and posterior in respect to the right ventricular outflow tract (RVOT). The angle between the aortic root and the RVOT is approximately 40–60◦ (Figure1B), while the line joining the nadir of the aortic sinuses lies in a plane that is tilted on its left of 30◦ in respect to the horizontal line. As a consequence, the left coronary sinus and its leaflet are at the highest position among the three sinuses (Figure1C). On its right lateral aspect, the aortic root is surrounded by the right atrial appendage (Figure1D), while posteriorly a space, called “sinus transversum”, separates the AO from the left atrial cavities. Adipose tissue is located at both the aortic and atrial side of the sinus (Figure1E). The close proximity of the non-coronary sinus to the fossa ovalis (FO) is well known to interventionalists. Indeed, puncturing the FO or implanting a device for a patent foramen ovalis or secundum atrial septal defect closure may injure the aortic wall, especially if the aortic root is enlarged [17] (Figure1F). In conclusion, the AO comes into contact with the right atrium, left atrium, interatrial septum, RVOT, mitral valve (aorto–mitral continuity), pulmonary valve, tricuspid valve, and conduction system (see below).

3.3. The Components of the Aortic Root The aortic root is composed of five key components: the ventricular–arterial junction (VAJ), the crown-shaped hinge of the semilunar leaflets (also called annulus), the leaflets, the sinuses, and the sinutubular junction (STJ).

3.3.1. The Ventricular–Arterial Junction (VAJ) The VAJ refers to an area where the left ventricular outflow tract (LVOT) joins the fibro-elastic wall of the AO. Differently from the right VAJ, which is entirely muscular, the left VAJ is in part muscular and in part fibrous.

3.3.2. The Muscular Component of VAJ The muscular tissue of VAJ represents nearly 45% of the entire VAJ. Interestingly, there is not an abrupt transition line between the ventricular myocardium and the aortic sinuses, on the contrary, the muscular component of the LVOT irregularly extends a few millimeters above the hinge lines of the right coronary leaflet (RCL) and the anterior part of left coronary leaflet (LCL) [18]. The hinge lines of the posterior part of the LCL and the non-coronary leaflet (NCL) are lacking myocardial fibers being in continuity with the anterior mitral leaflet and membranous septum. Hasdemir et al. [18] studied 95 human hearts, analyzing longitudinal strips of tissue containing each cusp, aortic, and pulmonary artery walls and left and right ventricular outflow tract. They found J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 5 of 20

Table 2. Functions of the aortic root.

Functions of Aortic Root Allowing the transit of a significant amount of blood with a minimum gradient between the left ventricle and the aorta Ensuring a wide flow variation (up to 5 times) Preventing significant back flow, having, at the same time, a robust structural integrity to withstand the aortic pressure Enabling an optimal coronary perfusion Preserving leaflet integrity

3.2. Aortic Root and Surrounding Structures

J. Cardiovasc. Dev. Dis. 2021, 8, 51 The AO is the cardiac “centerpiece” partially wedged between the atrioventricular5 of 18 orifices. (Figure 1A). Viewed from an antero-posterior plane, the aortic root is positioned to the right and posterior in respect to the right ventricular outflow tract (RVOT). The angle between the aortic root and the RVOT is approximately 40–60° (Figure 1B), while themuscular line joining fibers the in 7nadir out ofof 95the aortic aortic strips sinuses (7%) lies in in continuity a plane that with is thetilted underlying on its left LVOTof 30° inmuscle. respect In to around the horizontal 70% of cases, line. myocytesAs a conseq wereuence, mixed the withleft coronary fibrosis and sinus fatty and tissue. its leaflet The arearrangement at the highest where position electrically among active the three muscular sinuses fibers (Figure cover 1C). the On distal its right part lateral of the vesselsaspect, thein their aortic junction root is surrounded with the muscular by the right myocardium atrial appendage can also (Figure be found 1D), in while the pulmonaryposteriorly aveins space, [19 called], where “sinus they transversum”, may trigger abnormal separates electrical the AO from activity the and left atrial fibrillation.cavities. Adipose Since tissuea subgroup is located of outflow at both tract the aortic ventricular and atrial tachycardias side of the originate sinus (Figure fromthe 1E). aortic The close VAJ, itprox- can imitybe speculated of the non-coronary that, similarly sinus to to the the muscular fossa ovalis sleeves (FO) is around well known the pulmonary to interventionalists. veins, the Indeed,irregular puncturing mixture of the electrically FO or implanting active myocytes, a device fibrosis, for a patent and fat foramen may trigger ovalis ventricular or secun- dumarrhythmias atrial septal [20– 23defect]. In closure case ventricular may injure arrhythmias the aortic wall, require especially radiofrequency if the aortic catheter root is enlargedablation, [17] an in-depth (Figure 1F). understanding In conclusion, of thethe anatomicAO comes complexity into contact of with this regionthe right may atrium, help leftmaximize atrium, ablation interatrial success. septum, At theRVOT, same mitral time, valve the electrophysiologist (aorto–mitral continuity), should bepulmonary aware of valve,potential tricuspid complications valve, and when conduction operating system in this (see area below). (Figure 2).

Figure 1. (A) Computed tomographic image in multiplanar modality, showing the aortic root (AO) is the cardiac center- Figure 1. (A) Computed tomographic image in multiplanar modality, showing the aortic root (AO) is the cardiac centerpiece, piece, surrounded by the atria and the right ventricular outflow tract (RVOT). (B) The 3D volume rendering CT image in surrounded by the atria and the right ventricular outflow tract (RVOT). (B) The 3D volume rendering CT image in antero- posterior projection showing the obliquity of the aortic root (yellow arrow), sited posterior and rightward to the RVOT (red arrow). (C) Computed tomographic in multiplanar imaging modality showing the correct attitudinal orientation of the aorta. The black line, that joins the nadir of aortic sinuses, is near 30◦ tilted in respect to the horizontal red line, so that the left coronary sinus (LCS) and its leaflet are at the highest position among the right coronary (RCS) and non-coronary sinuses. (D) CT image in 3D volume rendering modality in antero-lateral projection showing the AO is surrounded laterally by the right atrial appendage (RAA). (E) CT image in 3D volume rendering modality in lateral projection, showing the space between the left atrium (LA) and the AO (yellow arrow) named “sinus transversum” filled up by epicardial adipose tissue. (F) The 2D transesophageal echocardiography in short-axis aortic view, showing the close proximity between the fossa ovalis (FO) and the non-coronary sinus (NCS) (see text). J. Cardiovasc. Dev.Dev. Dis. Dis.2021 2021, 8, ,8 51, x FOR PEER REVIEW 6 of 187 of 20

FigureFigure 2. 2.(A ()A CT) CT image image of short-axisof short-axis view view of the of aortic the aortic root from root an from aortic an perspective. aortic perspective. The gray-beige The gray- areasbeige superimposed areas superimposed to the image to the indicate image theindicate myocardium the myocardium enclosed atenclosed the bases atof the right bases coronary of right coronary sinus (RCS) and left coronary sinus (LCS). (B) CT scan of volumetric image of the aortic sinus (RCS) and left coronary sinus (LCS). (B) CT scan of volumetric image of the aortic root. The root. The ventriculo–arterial junction is indicated by the yellow dotted line. The red areas below ventriculo–arterial junction is indicated by the yellow dotted line. The red areas below indicate the indicate the muscular myocardium enclosed in the bottom part of the sinuses. (C) Cardiac mag- muscular myocardium enclosed in the bottom part of the sinuses. (C) Cardiac magnetic resonance netic resonance showing the left ventricle (LV), the left atrium (LA), and the aorta (AO) in cross- showing the left ventricle (LV), the left atrium (LA), and the aorta (AO) in cross-section long-axis section long-axis view. (D) Magnified image of the structures in the red square of the panel C. The view.double-headed (D) Magnified arrow image marks of the the structures extension in of the muscula red squarer sleeve of the on panelthe right C. The coronary double-headed sinus (RCS). arrow(E) Computed marks the tomography extension of showing muscular the sleeve LV, onthe the LA, right and coronarythe AO in sinus cross (RCS). section (E )long-axis Computed view. tomography(F) Magnified showing image the of LV, the the structures LA, and thein the AO red in cross square section of the long-axis panel C. view. The ( Fdouble-headed) Magnified image arrow ofmarks the structures the extension in the redof mu squarescular of sleeve the panel on C.the The RCS. double-headed arrow marks the extension of muscular sleeve on the RCS. During the ventricular filling phase and the isovolumetric contraction, the muscular During the ventricular filling phase and the isovolumetric contraction, the muscular component of the VAJ expands (together with the STJ), making the aortic root larger in component of the VAJ expands (together with the STJ), making the aortic root larger order to accommodate the stroke volume. This expansion reduces the area of leaflet coap- in order to accommodate the stroke volume. This expansion reduces the area of leaflet coaptationtation and and at the at the time time of oftheir their opening, opening, the the leaflets leaflets are are in in apposition onlyonly withwith their their free freeedge, edge, reducing reducing the the leaflet-to-leaflet leaflet-to-leaflet friction. friction. During During the the ejection, ejection, the the VAJ VAJ contracts, contracts, while whilethe STJ the continues STJ continues to expand. to expand. The The shape shape of ofthe the aortic aortic root root becomes becomes a a truncated truncated conecone with withthe smaller the smaller opening opening toward toward the theventricle ventricle facilitating facilitating the the progression progression of ofthe the blood blood column columntowards towards the ascending the ascending aorta. aorta. The Thefine fine sequen sequentialtial movement movement of of the the root root components dur- duringing systolic systolic ejection ejection resembles resembles thethe peristalsisperistalsis in in the the gut, gut, and and it is it meant is meant to optimize to optimize the the efficiencyefficiency of of the the system system and and reduce reduce the the stress stress on the on structuresthe structures [24]. [24].

3.4. The Fibrous Component of VAJ

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3.4. The Fibrous Component of VAJ The fibrous component represents nearly 55% of the entire VAJ and includes the mitral–aortic (MA) curtain, a fibrous avascular area located between the left (LCS) and the non-coronary sinus (NCS), and the membranous septum (MS) located between the NCS and the right coronary (RCS) sinuses. The MA curtain is well known to surgeons and cardiac imagers. Indeed, this area is often a target of aortic endocarditis (either on native leaflets or on aortic prostheses). The infection propagates by direct continuity of the aortic infected tissue or by infected regurgi- tant jet striking this area. The uncontrolled infection usually perforates the MA curtain, dissecting the aortic wall and propagating around the aortic root. A direct communication with the LVOT is often present, while a true enclosed abscess cavity very rarely develops and often a fistulous communication to other cardiac chambers can be recognized. In almost all cases the diagnosis is made by 2D TEE [25]. The peri-annular aortic abscess is a life-threatening condition since it may disrupt the fibrous skeleton and the atrioventricular J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 9 of 20 septum, making the reconstructive procedure very complicated (Figure3A,B) [26–28].

Figure 3. (A) The 2D TEE in long axis-view showing a peri-annular aortic abscess (arrow). (B) Same case of panel A show- Figure 3.ing(A the) The abscess 2D TEE may in extend long posteriorly axis-view on showing the crux a cordis peri-annular (arrow). aortic(C) The abscess 3D TEE (arrow).in long-axis (B )view. Same The case red of curve panel lines A showing the abscessmark may the extendposition posteriorlyof His bundle on immediately the crux cordis under (arrow).the MS (asterisk) (C) The and 3D its TEE bifurcation. in long-axis (D) CT view. multiplanar The red reconstruc- curve lines mark the positiontion showing of His bundlethe course immediately of the His bundle under and the its MSbranches (asterisk) (red lines). and The itsbifurcation. light blue cylinders (D) CT are multiplanar representative reconstruction of the position of the implanted valve. AO = aorta; LV = left ventricle; LA = left atrium; RA = right atrium; RV = right ventricle. showing the course of the His bundle and its branches (red lines). The light blue cylinders are representative of the position of the implanted valve. AO = aorta; LV = left ventricle; LA = left atrium; RA = right atrium; RV = right ventricle.

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Transcatheter implantation of the aortic valve (TAVI) is now recognized as state-of- the-art for patients with severe aortic stenosis and high risk for surgery. Recently, increased operator experience and enhanced transcatheter valve systems have led to a worldwide trend to use TAVI in patients who are at intermediate or low risk [29]. However, TAVI has an increased risk of injuring the atrio-ventricular conduction system. This is due to the close anatomical relationship between the aortic valve and the heart conduction system. Three major variants of AV nodes have been described, with 50% of individuals exhibiting a relatively right-sided AV bundle and 30% with a left-sided AV bundle, whereas in about 20% of patients the bundle courses under the membranous septum just below the endocardium. The last two above-described variants may expose patients to a higher risk of TAVI-induced conduction disturbances, especially in patients with a short membranous septum [29]. Today, the imaging of the membranous septum by CT scan prior to TAVI is a standard step to assess the risk of AV block after TAVI. The longer the length of the membranous septum, the lower the risk of post-TAVI AV conduction abnormalities [30]. According to the valve academic consortium, the development of post-procedural conduction disturbances may

J. Cardiovasc.not Dev.be Dis. the2021, strongest8, x FOR PEER REVIEW predictor of mortality but has a significant influence on long-term10 of 20 prognosis and the patient’s quality of life [31] (Figure3C,D). Figure4 shows an anatomic specimen with the components of the VAJ.

Figure 4. Anatomic specimen components of the aortic root: the sinus–tubular junction (white Figure 4. Anatomic specimen components of the aortic root: the sinus–tubular junction (white thick dotted line), the crown-shapedthick dotted annulus line), (red the dotted crown-shaped line), and the annulusventricular–arterial (red dotted junction line), (black and dotted the ventricular–arterial line). The virtual basal junctionring (white(black thin dotted dotted line). line). MS = membranous The virtual septum; basal ILT ring = interleaflet (white thin triangle. dotted line). MS = membranous septum; ILT = interleaflet triangle. 3.5. The Aortic Annulus There are different interpretations of the aortic annulus depending on whether you 3.5. The Aortic Annulusare an echocardiographer, a cardiac surgeon, or a pathologist. Since the beginning of the There are differentbidimensional interpretations echocardiographic of the aorticera, annula annulusr measurements depending have on been whether routinely you per- are an echocardiographer,formed aon cardiac 2D TEE surgeon, in the parasternal or a pathologist. long-axis view. Since More the recently, beginning using of2D the TEE, bidi- the aortic annuls is measured in a 120–140° long-axis view of the ventricle. These measure- mensional echocardiographicments are taken era,on mid annular systole measurementsat the basal attachment have of been adjacent routinely leaflets. performed In the TAVI on 2D TEE in theera, parasternal a “virtual” long-axis annulus isview. obtained More by joining recently, the usinglower points 2D TEE, of the the three aortic leaflets annuls (the is measured in aterm 120–140 “virtual”◦ long-axis refers to the view fact of that the this ventricle. “circumferential” These annulus measurements does not exist are neither taken on mid systole atanatomically the basal nor attachment histologically). of adjacentWhen measured leaflets. with In CT the multiplanar TAVI era, imaging a “virtual” or with 3D TEE, this “virtual annulus” has an elliptic shape in diastole and a more circular shape annulus is obtained by joining the lower points of the three leaflets (the term “virtual” in systole. Interestingly, since the lowest points of the three leaflets do not lie on the same plane, dedicated software reconstructs the virtual annuls as if it was lying in one plane. Though CT is considered the main imaging modality for identifying the correct size of the prosthesis [32], 3D TTE may be a valid imaging alternative in patients unsuitable for MDCT. Tamborini et al. [33] showed that 3D TTE measurements were highly reproduci- ble, and the agreement between 3D TTE and CT was very good (k = 0.84, p < 0.001) (Figure 5).

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refers to the fact that this “circumferential” annulus does not exist neither anatomically nor histologically). When measured with CT multiplanar imaging or with 3D TEE, this “virtual annulus” has an elliptic shape in diastole and a more circular shape in systole. Interestingly, since the lowest points of the three leaflets do not lie on the same plane, dedicated software reconstructs the virtual annuls as if it was lying in one plane. Though CT is considered the main imaging modality for identifying the correct size of the prosthesis [32], 3D TTE may be a valid imaging alternative in patients unsuitable for MDCT. Tamborini et al. [33]

J. Cardiovasc. Dev. Dis. 2021, 8, x FORshowed PEER REVIEW that 3D TTE measurements were highly reproducible, and the agreement11 of 20 between 3D TTE and CT was very good (k = 0.84, p < 0.001) (Figure5).

Figure 5. (A) The 2D and (B) 3D TEE long-axis view showing the echocardiographic annulus. Figure 5. (A) The 2D and (B) 3D TEE long-axis view showing the echocardiographic annulus. (C,D) (C,D) Multiplanar reconstruction using the 3D data set showing the virtual annulus. (E,F,H) CT Multiplanarscans showing reconstruction the 3 nadirs (marked using by the the 3D red, data green, set and showing yellow the circles). virtual (G) annulus.Dedicated (softwareE,F,H) CT scans showingaligns the the three 3 nadirsnadirs (markedin the same by plane the red,making green, possible and yellowmeasurements circles). of ( Gdiameters) Dedicated (white software dot- aligns theted threelines) nadirsand circumference in the same (blue plane line). making possible measurements of diameters (white dotted lines) and circumference (blue line). Even the so-called “surgical anulus” does not exist as a specific anatomical entity, once the diseased leaflets are removed, the prosthetic valve is sutured in a sort of “ring area”, which lies between the lowest part of the native leaflet hinge line and midway to the commissures. However, referring to this ring area as “annulus” is not illogical since it provides a precise reference point when the prosthesis is sutured in a supra-annular po- sition [34].

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Even the so-called “surgical anulus” does not exist as a specific anatomical entity, once the diseased leaflets are removed, the prosthetic valve is sutured in a sort of “ring area”, which lies between the lowest part of the native leaflet hinge line and midway to J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 12 of 20 the commissures. However, referring to this ring area as “annulus” is not illogical since it provides a precise reference point when the prosthesis is sutured in a supra-annular position [34]. Finally,Finally, from anan anatomicalanatomical point point of of view, view, the the aortic aortic annulus annulus is ais geometrically a geometrically complex com- plexthree-dimensional three-dimensional crown-shaped crown-shaped structure. structure. The insertionThe insertion of the of leaflets the leaflets on the on aortic the aortic wall, wall,in fact, in takesfact, takes the form the form of three of three prolonged prolonged coronets coronets with thewith lowest the lowest part (called part (called nadir) nadir) lying lyingslightly slightly below below the ventricular–arterial the ventricular–arterial junction junction and the highest and the point highest joining point the sinutubularjoining the sinutubularjunction. The junction. highest The joining highest point joining of two point adjacent of two leaflets adjacent is leaflets named is commissure. named commis- This sure.anatomical This anatomical arrangement arrangement guarantees guarantees a great flexibility a great flexibility that allows that the allows anulus the to anulus expand to expandduring theduring systole the minimizing systole minimizing the transvalvular the transvalvular gradient [35 gradient]. This flexibility [35]. This would flexibility not be possible in the presence of a circular fibrous ring, which should be robust and rigid enough would not be possible in the presence of a circular fibrous ring, which should be robust to withstand the diastolic aortic pressure. Such a ring-shaped annulus, on the other hand, and rigid enough to withstand the diastolic aortic pressure. Such a ring-shaped annulus, would have probably resulted in a fixed transvalvular gradient comparable to that present on the other hand, would have probably resulted in a fixed transvalvular gradient com- across a mechanical or a biological prosthesis (Figure6). parable to that present across a mechanical or a biological prosthesis (Figure 6).

Figure 6. (A) CT in volume rendering format and (B) 3D TEE showing the typical crown-shaped configuration of the Figure 6. (A) CT in volume rendering format and (B) 3D TEE showing the typical crown-shaped configuration of the anatomical annulus (dotted line). anatomical annulus (dotted line). 3.6. The Interleaflets Triangles 3.6. The Interleaflets Triangles The ventricular aspect of the aortic root is lined by three fibrous triangular extensions, The ventricular aspect of the aortic root is lined by three fibrous triangular extensions, filling the space between the hinge line of leaflets and extending from the VAJ to the com- filling the space between the hinge line of leaflets and extending from the VAJ to the missures [36]. The triangle between the left and right coronary leaflets is usually the small- commissures [36]. The triangle between the left and right coronary leaflets is usually the est, while the triangle between the left and the non-coronary leaflets is in continuity with smallest, while the triangle between the left and the non-coronary leaflets is in continuity the mitral–aortic curtain. The surgical relevance of this latter triangle relies on the fact that, with the mitral–aortic curtain. The surgical relevance of this latter triangle relies on the in a small aortic annulus (i.e., an annulus that cannot house a prosthesis size ≥21 mm), the fact that, in a small aortic annulus (i.e., an annulus that cannot house a prosthesis size annulus enlargement to accommodate a larger valve prosthesis may involve this anatom- ≥21 mm), the annulus enlargement to accommodate a larger valve prosthesis may involve ical portion of the root [37]. The surgical procedure consists in extending the aortotomic this anatomical portion of the root [37]. The surgical procedure consists in extending incision posteriorly through the commissure at the left and non-coronary sinus, cutting the aortotomic incision posteriorly through the commissure at the left and non-coronary this triangle up to the mitral–aortic curtain. Finally, the triangle between the non-coronary and the right coronary leaflets includes the MS, which marks the site of the atrioventricu- lar conduction bundle. Interestingly, all inter-leaflet triangles, despite anatomically con- sidered part of the aortic root, are subjected to ventricular pressures because they remain below the aortic valve leaflets (Figure 7).

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sinus, cutting this triangle up to the mitral–aortic curtain. Finally, the triangle between the non-coronary and the right coronary leaflets includes the MS, which marks the site of the atrioventricular conduction bundle. Interestingly, all inter-leaflet triangles, despite J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEERanatomically REVIEW considered part of the aortic root, are subjected to ventricular pressures13 of 20 because they remain below the aortic valve leaflets (Figure7).

Figure 7. The three inter-leaflets triangles visualized with CT volume rendering format (dotted line). NCS = non-coronary Figure 7. The three inter-leaflets triangles visualized with CT volume rendering format (dotted line). NCS = non-coronary sinus; LCS = left coronary sinus; RCS = right coronary sinus. sinus; LCS = left coronary sinus; RCS = right coronary sinus. 3.7. The Sinuses of Valsalva 3.7. The Sinuses of Valsalva The sinuses of Valsalva are bulges of the aortic root, one for each cusp in the tricuspid aorticThe valves. sinuses They of Valsalvaare named are according bulges of theto aorticthe coronary root, one arteries for each arising cusp infrom the tricuspidthem as rightaortic (RCS), valves. left They (LCS), are and named non-coronary according to(NCS) the coronary sinuses, arteriesand have arising different from sizes, them with as right the (RCS), left (LCS), and non-coronary (NCS) sinuses, and have different sizes, with the NCS NCS being the largest and the LCS the smallest. One function of the aortic sinuses is to being the largest and the LCS the smallest. One function of the aortic sinuses is to provide provide enough space behind the open leaflets to prevent the occlusion of the coronary enough space behind the open leaflets to prevent the occlusion of the coronary artery artery orifices. However, the main function of the sinuses is to preserve the integrity of orifices. However, the main function of the sinuses is to preserve the integrity of the aortic the aortic leaflets [38]. The most peripheral layers of blood flow, sliding along the ventric- leaflets [38]. The most peripheral layers of blood flow, sliding along the ventricular surface ular surface of the leaflets during systole, encounter the “bottle neck” of the sinutubular of the leaflets during systole, encounter the “bottle neck” of the sinutubular junction. These junction. These peripheral layers are then forced back into the space between the open peripheral layers are then forced back into the space between the open leaflets and the leaflets and the sinuses. By entering this space, the back flow creates a vortex that pro- sinuses. By entering this space, the back flow creates a vortex that promotes a slow closure motes a slow closure motion of leaflets, which approximate each other during the systole. motion of leaflets, which approximate each other during the systole. At the end of the At the end of the systole when the forward systolic flow still crosses the valve, the free systole when the forward systolic flow still crosses the valve, the free margins of the leaflets margins of the leaflets are already very close to each other. At the beginning of the dias- are already very close to each other. At the beginning of the diastole, when the blood tole,flow when reverses, the theblood distance flow betweenreverses, thethe valve distan leafletsce between is minimal, the valve ensuring leaflets a synchronous, is minimal, ensuringhomogeneous, a synchronous, and stress-free homogeneous, leaflet closure and st [39ress-free] (Figure leaflet8). closure [39] (Figure 8). Moreover, the presence of Valsalva sinuses may guarantee a progressive increase in the valve area and therefore an absence of gradient every time the cardiac output is increased (i.e., during an intense physical activity) [40]. During the systole, in fact, a progressive reduction of the pressure inside the sinuses (induced by the vortices) favors the increased flow across the valve. In other words, the lower pressure beyond the leaflets explains how the leaflet can reach and keep a wider opening area in an increased cardiac output maintaining a relatively low gradient. In the absence of sinuses, the aortic valve appears to be progressively more obstructive to the blood flow when the output increases. Indeed, the leaflets have less space for moving to their full opening position, and their free margin will show wrinkles and folds that might increase gradients and potentially contribute to an accelerated leaflet’s degeneration [41–43].

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FigureFigure 8. 8. (A(A–D–D) Tridimensional) Tridimensional 3D 3D TEE TEE showing showing the the progressive progressive closure closure of of aortic aortic leaflets leaflets during during the the systole. systole.

Moreover,The elastic the capability presence ofof theValsalva sinuses sinuse to distends may guarantee under pressure a progressive is another increase relevant in thecharacteristic valve area thatand preservestherefore thean absence leaflets integrity. of gradient A cross-section every time the in thecardiac middle output of the is body in- creasedof the sinuses(i.e., during reveals an that, intense in diastole, physical the activity) sinuses [40]. move During outward the assumingsystole, in a fact, three-lobed a pro- gressivearrangement. reduction This of diastolicthe pressure configuration inside the splitssinuses the (induced aortic root by the in three vortices) almost favors circular the increasedsinus–leaflet flow assembly across the units, valve. which In other are formed words, by the the lower sinus pressure and the correspondingbeyond the leaflets leaflet explainsand divided how the by theleaflet inter-leaflets’ can reach and triangles. keep a The wider stress opening on the area leaflets in an in increased diastole is cardiac almost outputfour times maintaining than in the a relatively sinuses, and low this gradient. would tetherIn the theabsence sinuses’ of sinuses, wall inwards. the aortic If this valve does appearsnot happen, to be progressively it is because thesemore sinus–leafletobstructive to assembly the bloodunits flow when adapt, the at output every single increases. beat, Indeed,to the diastolic the leaflets stress have conditions less space on for leaflets moving by to reducing their full theopening “radius position, of curvature” and their of free any marginsingle sinuswill show (in other wrinkles words and the folds sinus–leaflet that might assembly increase becomes gradients approximately and potentially spherical). con- tributeThis allows to an theaccelerated share of theleaflet’s diastolic degeneration circumferential [41–43]. stress between the leaflet and the sinus becomingThe elastic an enclosed capability self-sustained of the sinuses unit to that distend contains under the pressure pressure is within. another This relevant stress characteristicsharing preserves that preserves the longevity the leaflets of the integrity. aortic leaflets A cross-section [39,41,42]. in Interestingly, the middle of in the case body of a

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of the sinuses reveals that, in diastole, the sinuses move outward assuming a three-lobed arrangement. This diastolic configuration splits the aortic root in three almost circular si- nus–leaflet assembly units, which are formed by the sinus and the corresponding leaflet and divided by the inter-leaflets’ triangles. The stress on the leaflets in diastole is almost four times than in the sinuses, and this would tether the sinuses’ wall inwards. If this does not happen, it is because these sinus–leaflet assembly units adapt, at every single beat, to the diastolic stress conditions on leaflets by reducing the “radius of curvature” of any single sinus (in other words the sinus–leaflet assembly becomes approximately spherical). This allows the share of the diastolic circumferential stress between the leaflet and the J. Cardiovasc. Dev. Dis. 2021, 8, 51 sinus becoming an enclosed self-sustained unit that contains the pressure within.13 ofThis 18 stress sharing preserves the longevity of the aortic leaflets [39,41,42]. Interestingly, in case of a bicuspid aortic valve, this sophisticated stress-sharing architecture, resulting from bicuspidmillions aorticof years valve, of evolution, this sophisticated is lost. It stress-sharing is unsurprising architecture, that these resultingvalves are from predisposed millions ofto years an additional of evolution, circumferential is lost. It is stress unsurprising at an early that calcification these valves and are a worse predisposed outcome to [43]. an additional circumferential stress at an early calcification and a worse outcome [43]. 3.8. Leaflets 3.8. LeafletsThe aortic leaflets undoubtedly represent the “working component” of the aortic root. TheThe normal aortic aortic leaflets valve undoubtedly comprises three represent leaflets the with “working slight component differences” of in the size aortic and shape root. Themirroring normal the aortic coronary valve comprisessinuses: usually three leafletsthe non-coronary with slight leaflet differences (NCL) in is size the andlargest shape and mirroringthe left coronary the coronary leaflet sinuses: (LCL) usuallythe smallest, the non-coronary while the size leaflet of the (NCL) right is coronary the largest leaflets and the(RCL) left is coronary in between leaflet the (LCL) other the two. smallest, Each leaflet while has the several size of distinct the right anatomical coronary leafletsregions. (RCL)The hinge is in betweenline has thea crescent other two. shape Each being leaflet part has of several the crown-shaped distinct anatomical annulus regions. [14,15]. The The hingebody lineis the has skeleton a crescent of shapethe leaflet being bearing part of thethe crown-shapedmost force in annulusdiastole [when14,15 ].the The valve body is isclosed. the skeleton The lunula of the, which leaflet corresponds bearing the to most approximately force in diastole 30% of whenthe leaflet the valvetotal area, is closed. forms Thethe lunulaappositional, which surface corresponds between to approximatelyleaflets. In the middle 30% of theof the leaflet lunula total at area,the free forms margin, the appositionalthere is a thickened surface betweennodule called leaflets. the In Nodule the middle of Arantius of the. lunulaDuring at diastole, the free each margin, leaflet, there to- isgether a thickened with the nodule corresponding called the Nodulesinus, takes of Arantius the appearance. During diastole, of a bird’s each nest. leaflet, The togetherinsertion withline theof the corresponding leaflet is approximately sinus, takes the1.5 appearancetimes longer of than a bird’s the length nest. The of the insertion free margin, line of theand leafletthe height is approximately (base-margin) 1.5 ranges times longer between than 12 the and length 18 mm. of the A freeparticular margin, structure and the heightis often (base-margin)present on the ranges aged betweenleaflets: 12the and Lambl’s 18 mm. ex Acrescences particular (LEs) structure [44–47]. is often LEs presentare fibrous on thestrands aged typically leaflets: the occurring Lambl’s at excrescences coaptation surfaces (LEs) [44 of– 47the]. leaflets. LEs are These fibrous filiform strands fronds typically take occurringorigin from at coaptationsmall thrombi surfaces and fibrin of the depositi leaflets.on These on the filiform endocardial fronds surfaces take origin (where from the smallvalve thrombi margins and contact) fibrin as deposition a result of on micro the endocardial injuries. Over surfaces time, (where this fibrin–thrombi the valve margins depot contact)overgrows as a in result thin papillae of micro and injuries. eventually Over time,in thin, this mobile fibrin–thrombi strands made depot up overgrowsof a dense core in thinof collagenous papillae and and eventually elastic infibrils thin, enclosed mobile strands by endothelium. made up of LEs a dense are coreusually of collagenous found inci- anddentally elastic in fibrils otherwise enclosed asymptomatic by endothelium. aged LEspatients are usually and only found rarely incidentally it can be in the otherwise cause of asymptomaticstroke or coronary aged artery patients obstruction/occlusio and only rarely it cann as be opposed the cause to ofthe stroke fibroelastomas or coronary [48] artery (Fig- obstruction/occlusion as opposed to the fibroelastomas [48] (Figure9). ure 9).

Figure 9. (A) The 3D TEE magnified image showing the bird’s nest appearance with the lunula, body, and hinge line. (B) Anatomic specimens showing the Lambl’s excrescences (arrow).

As for atrio-ventricular valves, aortic leaflets are roughly composed of three layers covered, on both sides, by endothelium. This latter is a natural barrier for inflammatory cell infiltration or lipid accumulation and regulates permeability and cell adhesions by paracrine signals. The so-called lamina fibrosa is a layer of dense collagen fibers located beneath the aortic surface of the leaflets and arranged in a circumferential fashion. The collagen fibers of the lamina of each leaflet curve into the wall of the corresponding sinus, merging with elastic and muscular layers. This structural architecture reinforces the concept that the leaflet and sinus may be considered as an anatomical and functional unit. Individual leaflets are therefore suspended from their relative sinus almost totally by means of lamina fibrosa. Interestingly, these collagen fibers have an “undulating” radial J. Cardiovasc. Dev. Dis. 2021, 8, 51 14 of 18

arrangement. During the cardiac cycle, the leaflet area is about 50% larger in diastole compared to systole. Given its particular collagen fiber arrangement, the fibrosa can be easily “stretched” in diastole and “wrinkled” in systole. The ventricularis is made up predominantly by elastic fibers. This elastic lamina, being stretched in diastole and recoiled in systole, concurs with the fibrosa to expand the surface of the leaflets under diastolic pressure in order to prevent leaks through the coaptation surface. Interesting is the role of the spongiosa, a layer of loose connective tissue situated in between the other two layers. The spongiosa is the most complex of the three layers, being made up by sparse elastin and collagen fibers and by a rich extracellular matrix comprising complex glycoproteins, a network of nerve fibers and capillaries, and an array of different cell types, among which the most representative are the valvular interstitial cells (VICs). Each component of the spongiosa confers specific physical properties. Elastin allows recoil after each deformation, and glycoproteins provide a sort of “lubricant”, which reduces mechanical and frictional stress. Final VICs are essential in the regeneration process and damage repair. The continuous renewal of all components is one of the secrets of the leaflet’s longevity [48].

3.9. The Sinutubular Junction The sinutubular junction (STJ) is the distal part of the aortic root, between the aortic sinuses and the tubular segment of the ascending aorta. Contrary to the other “virtual” rings, the STJ is a true ring made up by circumferentially aligned fibro-elastic lamellae as a mild waist. This fibrous-elastic ring is more pronounced in the proximity of the attachments of the three commissures. Because of the strict proximity of the STJ with the commissures, this fibrous-elastic ring is an integral part of the valvular mechanism. The aortic valve insufficiency associated with the aneurysm of the aortic root, is due to the stretch of the STJ and commissures (which are dragged away from each other), that causes the tethering on the aortic leaflets and, as a consequence, a reduced systolic and diastolic excursion. As mentioned above, the STJ plays a role in generating the vortex behind the aortic leaflets [14,15].

3.10. The Coronary Ostia The preferential location of the coronary ostia is immediately below the STJ, arising from the maximum curvature of the sinus. Muriago et al. studied 23 normal hearts from autopsies in adults. They found that the left coronary artery arose within the left coronary aortic sinus in 16 (69%) specimens, above the sinutubular junction in 5 (22%), and at the level of the junction in 2 (9%). The right coronary artery arose within the right coronary aortic sinus in 18 (78%) specimens, above the junction in 3 (13%), and at the level of the junction in 2 (9%). Interestingly, accessory coronary orifices are found in the majority of the right coronary sinuses [49] (Figure 10A,B). The position of the coronary ostia above the virtual annulus has relevant clinical implication both in aortic root replacement, where the coronary ostia reimplantation is a key stage of the operation, [50] and in TAVI procedures [51,52], also including the valve in valve implantation [53]. In TAVI procedures, the coronary ostia may be obstructed either by the implanted aortic stent valve itself, or by the displacement of leaflet calcifications into the coronary lumen. The incidence of this complication in patients treated with balloon expandable devices is higher (1.1%) than in those treated with self-expanding valves (0.4%) [54]. The occurrence of coronary obstruction is also high in valve-in-valve TAVI procedures (2.3%), especially when the failed bioprosthesis features externally-mounted valve leaflets [53]. In the absence of defined guidelines, the currently recommended minimum distance of the coronary ostia from the aortic annulus is 10 mm [54]. Although CT is the main modality to identify coronary ostia [55] (Figure 10C,D), 3D TEE is also a valid alternative [56] (Figure 10E,F). Thus, a pre-procedural evaluation with CT or 3D TEE of the coronary ostia position (relative to the virtual annulus and aortic leaflets) is mandatory to minimize the risk of this rare but potentially life-threatening complication. J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 17 of 20

valve implantation [53]. In TAVI procedures, the coronary ostia may be obstructed either by the implanted aortic stent valve itself, or by the displacement of leaflet calcifications into the coronary lumen. The incidence of this complication in patients treated with bal- loon expandable devices is higher (1.1%) than in those treated with self-expanding valves (0.4%) [54]. The occurrence of coronary obstruction is also high in valve-in-valve TAVI procedures (2.3%), especially when the failed bioprosthesis features externally-mounted valve leaflets [53]. In the absence of defined guidelines, the currently recommended min- imum distance of the coronary ostia from the aortic annulus is 10 mm [54]. Although CT is the main modality to identify coronary ostia [55] (Figure 10C,D), 3D TEE is also a valid J. Cardiovasc. Dev. Dis. 2021, 8, 51 alternative [56] (Figure 10E,F). Thus, a pre-procedural evaluation with CT or 3D 15TEE of 18of the coronary ostia position (relative to the virtual annulus and aortic leaflets) is mandatory to minimize the risk of this rare but potentially life-threatening complication.

Figure 10. (A) CT Volume rendering modality showing the origin of right coronary artery arise at Figure 10. (A) CT Volume rendering modality showing the origin of right coronary artery arise at the the level of sinutubular junction (black dotted line). (B) The 3D TEE longitudinal cross-section level of sinutubular junction (black dotted line). (B) The 3D TEE longitudinal cross-section showing showing the orifice of coronary artery (arrow) at level of sinutubular junction (white dotted line). the(C,D orifice) CT multiplanar of coronary image artery modality (arrow) atshowing level of the sinutubular measurements junction of the (white distance dotted (double-headed line). (C,D) CTarrow) multiplanar between image the coronary modality ostia showing (white the dotted measurements line) and the of thevirtual distance annulus (double-headed (yellow dotted arrow) line). between(E) The 2D the TEE coronary multiplanar ostia (white reconstruc dottedtion line) derived and the by virtual 3D data annulus set in short-axis (yellow dotted view line).of the ( Eaorta) The 2Dshowing TEE multiplanar the orifice reconstructionof LAD (curved derived arrow). by The 3D datawhit sete dotted in short-axis line indicates view of the the longitudinal aorta showing cross- the orificesection of plane LAD that (curved shows arrow). the image The white of the dotted panel. line(F) From indicates this theimage, longitudinal the distance cross-section between the plane thatcoronary shows ostia the image (white of dotted the panel. line) (F and) From the thisvirt image,ual annulus the distance (yellow between dotted line) the coronary can be measured ostia (white dotted(double-headed line) and the arrows). virtual annulus (yellow dotted line) can be measured (double-headed arrows). 4. Conclusions The 3D-TEE, CT, and CMR provide excellent images of a “dynamic” aortic root anatomy, both in two- and three-dimensional format that admirably joins structure and function. This review describes the components of the aortic root, specifically the sinu- tubular junction, the crown-shaped aortic annulus, the Valsalva’s sinuses, the leaflets, the STJ, and the position of the coronary ostia as revealed by non-invasive imaging techniques. Nowadays, new portable echocardiographic machines, as small and light as a cell phone, are available and likely will substitute the stethoscope in the coming years showing the heart and valves in real time (does the word “stethoscope” not derive from the ancient Greek words στηθóυς (stetheos), which means chest, and σκoπεω (skopeo), which means look into?). With the highest spatial resolution power and ultra-low radiation exposure, the new CT machines are able to depict cardiac anatomical details that were unthinkable just a few years ago. Moreover, latest advances in 3D CT reconstruction techniques can J. Cardiovasc. Dev. Dis. 2021, 8, 51 16 of 18

now visualize the very nuance of the 3D living anatomy with greater spatial resolution and wide field of view compared with echocardiography [12,13]. Finally, the new CMR offers superb anatomic imaging, tissue structures, and flow imaging in a unique examination. We strongly believe that in the third millennium, medical students and, in particular, cardi- ologists will learn the cardiac anatomy using these powerful imaging tools. We hope that this review will also serve this aim.

Funding: This research received no external funding. Conflicts of Interest: Francesco F Faletra speaker fees from Philips. Francesco Maisano: Grant and/or Research Institutional Support from Abbott, Medtronic, Edwards Lifesciences, Biotronik, Boston Scientific Corporation, NVT, Terumo. Consulting fees, Honoraria personal and Institutional from Abbott, Medtronic, Edwards Lifesciences, Xeltis, Cardiovalve, Occlufit, Simulands. Royalty Income/IP Rights Edwards Lifesciences. Shareholder (including share options) of Cardiogard, Magenta, SwissVortex, Transseptalsolutions, Occlufit, 4Tech, Perifect.

References 1. Faletra, F.F.; Leo, L.A.; Paiocchi, V.L.; Caretta, A.; Viani, G.M.; Schlossbauer, S.A.; Demertzis, S.; Ho, S.Y. Anatomy of Mitral Annulus Insights from Non-Invasive Imaging Techniques. Eur. Heart J. Cardiovasc. Imaging 2019, 20, 843–857. [CrossRef] [PubMed] 2. Faletra, F.F.; Leo, L.A.; Paiocchi, V.; Schlossbauer, S.; Narula, J.; Ho, S.Y. Multimodality Imaging Anatomy of Interatrial Septum and Mitral Annulus. Heart 2020.[CrossRef] 3. Leo, L.A.; Paiocchi, V.L.; Schlossbauer, S.A.; Gherbesi, E.; Faletra, F.F. Anatomy of Mitral Valve Complex as Revealed by Non-Invasive Imaging: Pathological, Surgical and Interventional Implications. J. Cardiovasc. Dev. Dis. 2020, 7, 49. [CrossRef] 4. Faletra, F.F.; Leo, L.A.; Paiocchi, V.L.; Schlossbauer, S.A.; Pedrazzini, G.; Moccetti, T.; Ho, S.Y. Revisiting Anatomy of the Interatrial Septum and its Adjoining Atrioventricular Junction Using Noninvasive Imaging Techniques. J. Am. Soc. Echocardiogr. 2019, 32, 580–592. [CrossRef] 5. Saremi, F.; Hassani, C.; Sánchez-Quintana, D. Septal Atrioventricular Junction Region: Comprehensive Imaging in Adults. Radiography 2016, 36, 1966–1986. [CrossRef] 6. Yasunaga, D.; Hamon, M. MDCT of Interatrial Septum. Diagn. Interv. Imaging 2015, 96, 891–899. [CrossRef][PubMed] 7. Hassani, C.; Saremi, F. Comprehensive Cross-sectional Imaging of the Pulmonary Veins. Radiography 2017, 37, 1928–1954. [CrossRef][PubMed] 8. Sánchez-Quintana, D.; López-Mínguez, J.R.; Macías, Y.; Cabrera, J.A.; Saremi, S. Left Atrial Anatomy relevant to Catheter Ablation. Cardiol. Res. Pract. 2014, 2014, 289720. [CrossRef][PubMed] 9. Sánchez-Quintana, D.; Doblado-Calatrava, M.; Cabrera, J.A.; Macías, Y.; Saremi, F. Anatomical Basis for the Cardiac Interventional Electrophysiologist. Biomed. Res. Int. 2015, 2015, 547364. [CrossRef][PubMed] 10. David, T.E.; Feindel, C.M. An Aortic Valve-Sparing Operation for Patients with Aortic Incompetence and Aneurysm of the Ascending Aorta. J. Thorac. Cardiovasc. Surg. 1992, 103, 617–621. [CrossRef] 11. Cribier, A.; Eltchaninoff, H.; Bash, A.; Borenstein, N.; Tron, C.; Bauer, F.; Derumeaux, G.; Anselme, F.; Laborde, F.; Leon, M.B. Percutaneous Transcatheter Implantation of an Aortic Valve Prosthesis for Calcific Aortic Stenosis: First Human Case Description. Circulation 2002, 106, 3006–3008. [CrossRef][PubMed] 12. Mori, S.; Tretter, J.T.; Spicer, D.E.; Bolender, D.L.; Anderson, R.H. What Is the Real Cardiac Anatomy? Clin. Anat. 2019, 32, 288–309. [CrossRef][PubMed] 13. Mori, S.; Izawa, Y.; Shimoyama, S.; Tretter, J.T. Three-Dimensional Understanding of Complexity of the Aortic Root Anatomy as the Basis of Routine Two-Dimensional Echocardiographic Measurements. Circ. J. 2019, 83, 2320–2323. [CrossRef][PubMed] 14. Ho, S.Y. Structure and Anatomy of the Aortic Root. Eur. J. Echocardiogr. 2009, 10, i3–i10. 15. Anderson, R.H. Clinical Anatomy of the Aortic Root. Heart 2000, 84, 670–675. [PubMed] 16. Koshkelashvili, N.; Jalife Bucay, M.; Goykhman, I. Pressman GS. Aortic root and Valve Proportions: An Example of the Golden Ratio? Monaldi Arch. Chest. Dis. 2019, 89.[CrossRef] 17. O’Brien, B.; Zafar, H.; De Freitas, S.; Sharif, F. Transseptal Puncture—Review of Anatomy, Techniques, Complications and Challenges. Int. J. Cardiol. 2017, 233, 12–22. [PubMed] 18. Hasdemir, C.; Aktas, S.; Govsa, F.; Aktas, E.O.; Kocak, A.; Bozkaya, Y.T.; Demirbas, M.I.; Ulucan, C.; Ozdogan, O.; Kayikcioglu, M.; et al. Demonstration of Ventricular Myocardial Extensions into the Pulmonary Artery and Aorta Beyond the Ventriculo-Arterial Junction. Pacing. Clin. Electrophysiol. 2007, 30, 534–539. [CrossRef] 19. Ho, S.Y.; Cabrera, J.A.; Tran, V.H.; Farré, J.; Anderson, R.H.; Sánchez-Quintana, D. Architecture of the Pulmonary Veins: Relevance to Radiofrequency Ablation. Heart 2001, 86, 265–270. [CrossRef] 20. Yamada, T.; Litovsky, S.H.; Kay, G.N. The Left Ventricular Ostium: An Anatomic Concept Relevant to Idiopathic Ventricular Arrhythmias. Circ. Arrhythm. Electrophysiol. 2008, 1, 396–404. [CrossRef] J. Cardiovasc. Dev. Dis. 2021, 8, 51 17 of 18

21. Hlivák, P.; Peichl, P.; Cihák, R.; Wichterle, D.; Kautzner, J. Catheter Ablation of Idiopathic Ventricular Tachycardia Originating from Myocardial Extensions into a Noncoronary Aortic Cusp. J. Cardiovasc. Electrophysiol. 2012, 23, 98–101. [CrossRef] 22. Gard, J.J.; Asirvatham, S.J. Outflow Tract Ventricular Tachycardia. Tex. Heart. Inst. J. 2012, 39, 526–5288. [PubMed] 23. Asirvatham, S.J. Correlative Anatomy for the Invasive Electrophysiologist: Outflow Tract and Supravalvar Arrhythmia. J. Cardiovasc. Electrophysiol. 2009, 20, 955–968. [CrossRef][PubMed] 24. Cheng, A.; Dagum, P.; Miller, D.C. Aortic Root Dynamics and Surgery: From Craft to Science. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 2007, 362, 1407–1419. [CrossRef][PubMed] 25. Brecker, S.J.; Jin, X.Y.; Yacoub, M.H. Anatomical Definition of Aortic Root Abscesses by Transesophageal Echocardiography: Planning a Surgical Strategy Using Homograft Valves. Clin. Cardiol. 1995, 18, 353–359. [CrossRef][PubMed] 26. Oh, H.K.; Kim, N.Y.; Kang, M.W.; Kang, S.K.; Yu, J.H.; Lim, S.P.; Choi, J.S.; Na, M.H. Aortic Periannular Abscess Invading into the Central Fibrous Body, Mitral Valve, and Tricuspid Valve. Korean J. Thorac. Cardiovasc. Surg. 2014, 47, 283–286. [CrossRef] 27. Parish, L.M.; Liu, L.; Woo, Y.J. Endocarditis with Massive Aortic Root Abscess and Atrioventricular Septal Destruction. Interact. Cardiovasc. Thorac. Surg. 2009, 8, 280–282. [CrossRef][PubMed] 28. Vipparthy, S.C.; Ravi, V.; Avula, S.; Kambhatla, S.; Mahmood, M.; Kabour, A.; Ali, S.S.; Barzallo, M.; Mungee, S. Meta-Analysis of Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Patients with Low Surgical Risk. Am. J. Cardiol. 2020, 125, 459–468. [CrossRef] 29. Kawashima, T.; Sato, F. Visualizing Anatomical Evidences on Atrioventricular Conduction System for TAVI. Int. J. Cardiol. 2014, 174, 1–6. [CrossRef] 30. Jilaihawi, H.; Zhao, Z.; Du, R.; Staniloae, C.; Saric, M.; Neuburger, P.J.; Querijero, M.; Vainrib, A.; Hisamoto, K.; Ibrahim, H.; et al. Minimizing Permanent Pacemaker Following Repositionable Self-Expanding Transcatheter Aortic Valve Replacement. JACC Cardiovasc. Interv. 2019, 12, 1796–1807. [CrossRef] 31. Kappetein, A.P.; Head, S.J.; Généreux, P.; Piazza, N.; van Mieghem, N.M.; Blackstone, E.H.; Brott, T.G.; Cohen, D.J.; Cutlip, D.E.; van Es, G.A.; et al. Updated Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation: The Valve Academic Research Consortium-2 Consensus Document. J. Am. Coll. Cardiol. 2012, 60, 1438–1454. [CrossRef][PubMed] 32. Pontone, G.; Andreini, D.; Bartorelli, A.L.; Bertella, E.; Cortinovis, S.; Mushtaq, S.; Annoni, A.; Formenti, A.; Baggiano, A.; Conte, E.; et al. Aortic Annulus Area Assessment by Multidetector Computed Tomography for Predicting Paravalvular Regurgi- tation in Patients Undergoing Balloon-Expandable Transcatheter Aortic Valve Implantation: A Comparison with Transthoracic and Transesophageal Echocardiography. Am. Heart. J. 2012, 164, 576–584. 33. Tamborini, G.; Fusini, L.; Muratori, M.; Cefalù, C.; Gripari, P.; Ali, S.G.; Pontone, G.; Andreini, D.; Bartorelli, A.L.; Alamanni, F.; et al. Feasibility and Accuracy of Three-Dimensional Transthoracic Echocardiography vs. Multidetector Computed Tomography in the Evaluation of Aortic Valve Annulus in Patient Candidates to Transcatheter Aortic Valve Implantation. Eur. Heart J. Cardiovasc. Imaging. 2014, 15, 1316–1323. [CrossRef][PubMed] 34. Kim, S.H.; Kim, H.J.; Kim, J.B.; Jung, S.H.; Choo, S.J.; Chung, C.H.; Lee, J.W. Supra-Annular Versus Intra-Annular Prostheses in Aortic Valve Replacement: Impact on Haemodynamics and Clinical Outcomes. Interact. Cardiovasc. Thorac. Surg. 2019, 28, 58–64. [CrossRef][PubMed] 35. Suchá, D.; Tuncay, V.; Prakken, N.H.; Leiner, T.; van Ooijen, P.M.; Oudkerk, M.; Budde, R.P. Does the Aortic Annulus Undergo Conformational Change Throughout the Cardiac Cycle? A Systematic Review. Eur. Heart J. Cardiovasc. Imaging 2015, 16, 1307–1317. [CrossRef][PubMed] 36. Sutton, J.P.; Ho, S.Y.; Anderson, R.H. The Forgotten Interleaflet Triangles: A Review of Surgical Anatomy of the Aortic Valve. Ann. Thorac. Surg. 1995, 59, 419–427. [CrossRef] 37. Sá, M.P.B.O.; Zhigalov, K.; Cavalcanti, L.R.P.; Escorel Neto, A.C.; Rayol, S.C.; Weymann, A.; Ruhparwar, A.; Lima, R.C. Impact of Aortic Annulus Enlargement on the Outcomes of Aortic Valve Replacement: A Meta-Analysis. Semin. Thorac. Cardiovasc. Surg. 2020.[CrossRef][PubMed] 38. Katayama, S.; Umetani, N.; Sugiura, S.; Hisada, T. The Sinus of Valsalva Relieves Abnormal Stress on Aortic Valve Leaflets by Facilitating Smooth Closure. J. Thorac. Cardiovasc. Surg. 2008, 136, 1528–1535.e1. [CrossRef] 39. Pisani, G.; Scaffa, R.; Ieropoli, O.; Dell’Amico, E.M.; Maselli, D.; Morbiducci, U.; De Paulis, R. Role of the Sinuses of Valsalva on the Opening of the Aortic Valve. J. Thorac. Cardiovasc. Surg. 2013, 145, 999–1003. [CrossRef][PubMed] 40. Robicsek, F.; Thubrikar, M.J.; Fokin, A.A. Cause of Degenerative Disease of the Trileaflet Aortic Valve: Review of Subject and Presentation of a New Theory. Ann. Thorac. Surg. 2002, 73, 1346–1354. [CrossRef] 41. Underwood, M.J.; El Khoury, G.; Deronck, D.; Glineur, D.; Dion, R. The Aortic Root: Structure, Function, and Surgical Reconstruction. Heart 2000, 83, 376–380. [CrossRef] 42. Thubrikar, M.J.; Nolan, S.P.; Aouad, J.; Deck, J.D. Stress Sharing between the Sinus and Leaflets of Canine Aortic Valve. Ann. Thorac. Surg. 1986, 42, 434–440. [CrossRef] 43. Tzemos, N.; Therrien, J.; Yip, J.; Thanassoulis, G.; Tremblay, S.; Jamorski, M.T.; Webb, G.D.; Siu, S.C. Outcomes in Adults with Bicuspid Aortic Valves. JAMA 2008, 300, 1317–1325. [CrossRef] 44. Ammannaya, G.K.K. Lambl’s Excrescences: Current Diagnosis and Management. Cardiol. Res. 2019, 10, 207–210. [CrossRef] 45. Nighoghossian, N.; Trouillas, P.; Perinetti, M.; Barthelet, M.; Ninet, J.; Loire, R. Excroissance de Lambl: Une Cause Inhabituelle D’embolie Cérébrale [Lambl’s Excrescence: An Uncommon Cause of Cerebral Embolism]. Rev. Neurol. 1995, 51, 583–585. J. Cardiovasc. Dev. Dis. 2021, 8, 51 18 of 18

46. Roldan, C.A.; Shively, B.K.; Crawford, M.H. Valve excrescences: Prevalence, Evolution and Risk for Cardioembolism. J. Am. Coll. Cardiol. 1997, 30, 1308–1314. [CrossRef] 47. Kalavakunta, J.K.; Peddi, P.; Bantu, V.; Tokala, H.; Kodenchery, M. Lambl’s Excrescences: A Rare Cause of Stroke. J. Heart Valve. Dis. 2010, 19, 669–670. [PubMed] 48. Schoen, F.J. Evolving Concepts of Cardiac Valve Dynamics: The Continuum of Development, Functional Structure, Pathobiology, and Tissue Engineering. Circulation 2008, 118, 1864–1880. [CrossRef][PubMed] 49. Muriago, M.; Sheppard, M.N.; Ho, S.Y.; Anderson, R.H. Location of the Coronary Arterial Orifices in The Normal Heart. Clin. Anat. 1997, 10, 297–302. [CrossRef] 50. Mariani, S.; Peek, G.J. Coronary Reimplantation in Aortic Root Surgery: The Trapdoor Technique for Adults. Ann. Thorac. Surg. 2015, 99, 1833–1834. [CrossRef] 51. Tatsuishi, W.; Nakano, K.L.; Kubota, S.; Asano, R.; Kataoka, G. Identification of Coronary Artery Orifice to Prevent Coronary Complications in Bioprosthetic and Transcatheter Aortic Valve Replacement. Circ. J. 2015, 79, 2157–2161. [CrossRef][PubMed] 52. Khatri, P.J.; Webb, J.G.; Rodés-Cabau, J.; Fremes, S.E.; Ruel, M.; Lau, K.; Guo, H.; Wijeysundera, H.C.; Ko, D.T. Adverse Effects Associated with Transcatheter Aortic Valve Implantation: A Meta-Analysis of Contemporary Studies. Ann. Intern. Med. 2013, 158, 35–46. [CrossRef] 53. Dvir, D.; Webb, J.; Brecker, S.; Bleiziffer, S.; Hildick-Smith, D.; Colombo, A.; Descoutures, F.; Hengstenberg, C.; Moat, N.E.; Bekeredjian, R.; et al. Transcatheter Aortic Valve Replacement for Degenerative Bioprosthetic Surgical Valves: Results from the Global Valve-In-Valve Registry. Circulation 2012, 126, 2335–2344. [CrossRef][PubMed] 54. Ribeiro, H.B.; Webb, J.G.; Makkar, R.R.; Cohen, M.G.; Kapadia, S.R.; Kodali, S.; Tamburino, C.; Barbanti, M.; Chakravarty, T.; Jilaihawi, H.; et al. Predictive Factors, Management, and Clinical Outcomes of Coronary Obstruction Following Transcatheter Aortic Valve Implantation: Insights from a Large Multicenter Registry. J. Am. Coll. Cardiol. 2013, 62, 1552–1562. [CrossRef] [PubMed] 55. Tops, L.F.; Wood, D.A.; Delgado, V.; Schuijf, J.D.; Mayo, J.R.; Pasupati, S.; Lamers, F.P.; van der Wall, E.E.; Schalij, M.J.; Webb, J.G.; et al. Noninvasive Evaluation of the Aortic Root with Multislice Computed Tomography Implications for Transcatheter Aortic Valve Replacement. JACC Cardiovasc. Imaging 2008, 1, 321–330. [CrossRef][PubMed] 56. Tamborini, G.; Fusini, L.; Gripari, P.; Muratori, M.; Cefalù, C.; Maffessanti, F.; Alamanni, F.; Bartorelli, A.; Pontone, G.; Andreini, D.; et al. Feasibility and Accuracy of 3DTEE Versus CT for the Evaluation of Aortic Valve Annulus to Left Main Ostium Distance before Transcatheter Aortic Valve Implantation. JACC Cardiovasc. Imaging 2012, 5, 579–588. [CrossRef][PubMed]