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The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve–related aortopathy: Full online-only version

Open ArchivePublished:May 15, 2018DOI:https://doi.org/10.1016/j.jtcvs.2018.02.115

      Abstract

      Bicuspid aortic valve disease is the most common congenital cardiac disorder, being present in 1% to 2% of the general population. Associated aortopathy is a common finding in patients with bicuspid aortic valve disease, with thoracic aortic dilation noted in approximately 40% of patients in referral centers. Several previous consensus statements and guidelines have addressed the management of bicuspid aortic valve–associated aortopathy, but none focused entirely on this disease process. The current guidelines cover all major aspects of bicuspid aortic valve aortopathy, including natural history, phenotypic expression, histology and molecular pathomechanisms, imaging, indications for surgery, surveillance, and follow-up, and recommendations for future research. It is intended to provide clinicians with a current and comprehensive review of bicuspid aortic valve aortopathy and to guide the daily management of these complex patients.
      Figure thumbnail fx1
      Typical patient with BAV and associated aortopathy.
      The current document is the full online-only version of “The American Association for Thoracic Surgery Consensus Guidelines on Bicuspid Aortic Valve–Related Aortopathy.”
      BAV-related aortopathy is a common clinical entity. An increasing amount of literature has recently shown that BAV aortopathy is less dangerous than previously described. The current document is a comprehensive review of BAV-related aortopathy and its management.

      1. Introduction

      Bicuspid aortic valve (BAV) disease is the most common congenital cardiac disorder, being present in 1% to 2% of the general population.
      • Hoffman J.
      • Kaplan S.
      The incidence of congenital heart disease.
      Associated aortopathy is a common finding in patients with BAV disease, with thoracic aortic dilation noted in approximately 40% of patients in referral centers.
      • Masri A.
      • Kalahasti V.
      • Alkharabsheh S.
      • Svensson L.G.
      • Sabik J.F.
      • Roselli E.E.
      • et al.
      Characteristics and long-term outcomes of contemporary patients with bicuspid aortic valves.
      The risk of acute aortic emergencies, most commonly aortic dissection, is higher in patients with BAV disease than in the general population.
      • Januzzi J.L.
      • Isselbacher E.M.
      • Fattori R.
      • Cooper J.V.
      • Smith D.E.
      • Fang J.
      • et al.
      Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD).
      Optimal timing of surgical intervention, to avoid aortic emergencies, is defined as that time point when the risk of conservative management exceeds the risk of surgery. However, precise determination of this time point is difficult and depends on several factors, including patient age, risk factors, comorbidities, family history, and presence or absence of significant aortic valvular disease.
      Historically, aortopathy observed in patients with BAV disease was thought to be no different than that associated with tricuspid aortic valve (TAV) disease. That is, aortic dilation was thought to be due to turbulent blood flow downstream from a stenotic aortic valve. In the 1990s and 2000s, however, several observations and studies led investigators to think that a strong genetic role contributed to BAV-associated aortopathy and that the risk of acute aortic complications was substantially increased in this patient population.
      • Fedak P.
      • David T.
      • Borger M.
      • Verma S.
      • Butany J.
      • Weisel R.
      Bicuspid aortic valve disease: recent insights in pathophysiology and treatment.
      Such hypotheses led to recommendations for a more aggressive surgical approach to this disease, with some suggesting that BAV aortopathy was roughly equivalent to Marfan syndrome.
      • Hiratzka L.F.
      • Bakris G.L.
      • Beckman J.A.
      • Bersin R.M.
      • Carr V.F.
      • Casey Jr., D.E.
      • et al.
      2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
      Subsequent studies and observations have led to a middle ground, however, suggesting that hemodynamic and genetic components play varying roles in different subgroups of patients with BAV
      • Girdauskas E.
      • Borger M.A.
      • Secknus M.A.
      • Girdauskas G.
      • Kuntze T.
      Is aortopathy in bicuspid aortic valve disease a congenital defect or a result of abnormal hemodynamics? A critical reappraisal of a one-sided argument.
      and that the risk of aortic emergencies is not as high as previously thought in this patient population.
      • Itagaki S.
      • Chikwe J.P.
      • Chiang Y.P.
      • Egorova N.N.
      • Adams D.H.
      Long-term risk for aortic complications after aortic valve replacement in patients with bicuspid aortic valve versus Marfan syndrome.
      • Sherrah A.G.
      • Andvik S.
      • van der Linde D.
      • Davies L.
      • Bannon P.G.
      • Padang R.
      • et al.
      Nonsyndromic thoracic aortic aneurysm and dissection: outcomes with Marfan syndrome versus bicuspid aortic valve aneurysm.
      Determination of the cause of BAV aortopathy is important because of the therapeutic implications for patients with isolated aneurysmal dilation of the aorta and in those undergoing aortic valve surgery for BAV disease.
      Several previous documents have addressed the management of BAV-associated aortopathy, with the first being a set of multisocietal guidelines published in 2010.
      • Hiratzka L.F.
      • Bakris G.L.
      • Beckman J.A.
      • Bersin R.M.
      • Carr V.F.
      • Casey Jr., D.E.
      • et al.
      2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
      This document made aggressive recommendations for the management of BAV aortopathy, grouping such patients in with Marfan and other connective tissue disorders. However, multiple studies reported since that time have provided new insights into the pathophysiology and mechanistic aspects of BAV aortopathy. As such, a more conservative set of recommendations was made in the more recently published valvular heart disease guidelines by the American Heart Association (AHA) and the American College of Cardiology (ACC).
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin III, J.P.
      • Guyton R.A.
      • et al.
      2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.
      The marked difference in the positions of these 2 sets of guidelines resulted in the recent publication of a clarification statement.
      • 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease Representative Members
      • Hiratzka L.F.
      • Creager M.A.
      • Isselbacher E.M.
      • Svensson L.G.
      • 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease Representative Members
      • et al.
      Surgery for aortic dilatation in patients with bicuspid aortic valves: a statement of clarification from the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      The European Society of Cardiology (ESC) also published guidelines on the management of valvular heart disease in 2012
      • Vahanian A.
      • Alfieri O.
      • Andreotti F.
      • Antunes M.J.
      • Baron-Esquivias G.
      • Baumgartner H.
      • et al.
      Guidelines on the management of valvular heart disease (version 2012): the joint task force on the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS).
      and aortic disease specifically in 2014.
      • Erbel R.
      • Aboyans V.
      • Boileau C.
      • Bossone E.
      • Bartolomeo R.D.
      • Eggebrecht H.
      • et al.
      2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).
      Both of these documents contained more conservative recommendations for BAV aortopathy, in line with the 2014 ACC/AHA guidelines.
      Of these publications, none focused entirely on patients with BAV aortopathy. Therefore, the current consensus statement differs in that it covers all major aspects of BAV aortopathy, including its natural history, phenotypic expression, histology and molecular pathomechanisms, imaging, indications for surgery, surveillance and follow-up, and recommendations for future research. Such research will hopefully lead to new insights into this common disease and the need for an update to the current consensus statement in a few years.
      BAV aortopathy is a markedly heterogeneous entity. Dilation may occur in the aortic root, the tubular ascending aorta, the proximal aortic arch, or any contiguous combination of these 3.
      • Fazel S.S.
      • Mallidi H.R.
      • Lee R.S.
      • Sheehan M.P.
      • Liang D.
      • Fleischman D.
      • et al.
      The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch.
      The current document uses the term “aortic root” to refer to the proximal aorta extending from the nadir of the aortic annulus to the sinotubular junction (STJ) including the coronary ostia. For purposes of consistency, the term “tubular aorta” (also known as the “supracoronary aorta”) is used to describe the area between the STJ and the takeoff of the brachiocephalic artery. The “aortic arch” refers to the area extending from the brachiocephalic to the left subclavian artery. In addition, the Sievers' classification
      • Sievers H.H.
      • Schmidtke C.
      A classification system for the bicuspid aortic valve from 304 surgical specimens.
      is used to describe BAV morphology (Figure 1). Although several different classification systems have been used to describe BAV morphology, the Sievers' system is the one that is used most commonly within the cardiac surgery literature. However, it is clear that a more comprehensive classification system that takes into consideration BAV morphology, BAV pathology (ie, stenosis, insufficiency, or mixed), and location and extent of associated BAV aortopathy is required.
      Figure thumbnail gr1
      Figure 1Sievers' classification system for BAV as viewed from the surgeon's side with the left coronary artery at left. The number of specimens is given, and the percentage is shown in parentheses. The blackened lines represent raphe. The main category is based on the number of raphes, the first subcategory is based on spatial position, and the second subcategory reflects valve function. Ap, Anterior-posterior; B, balanced valvular lesion; I, insufficiency; L, left coronary sinus; lat, lateral; N, noncoronary sinus; No, normal function; R, right coronary sinus; S, stenosis.
      Used with permission from Sievers and Schmidtke.
      • Sievers H.H.
      • Schmidtke C.
      A classification system for the bicuspid aortic valve from 304 surgical specimens.
      Because BAV aortopathy is a relatively common disorder, decisions regarding its therapeutic management must be made by cardiovascular clinicians on a regular basis. Despite this, there is significant confusion within the cardiovascular community regarding appropriate decision-making in this patient population.
      • Verma S.
      • Yanagawa B.
      • Kalra S.
      • Ruel M.
      • Peterson M.D.
      • Yamashita M.H.
      • et al.
      Knowledge, attitudes, and practice patterns in surgical management of bicuspid aortopathy: a survey of 100 cardiac surgeons.
      The confusion is not surprising, however, given the described differences in recommendations made by various societies and the shifting discussion on the cause and pathophysiology of BAV aortopathy. The purpose of this consensus statement is to provide clinicians with a current and comprehensive review of all major aspects of BAV aortopathy and to serve as a guide in the daily management of these complex patients.

      2. Epidemiology and Natural History

      Epidemiology

      Aortic enlargement and aneurysm formation, especially in the ascending aorta, are part and parcel of BAV disease—the so-called bicuspid aortopathy.

      Prevalence

      The prevalence of BAV in the general population is known to be 1% to 2%.
      • Hoffman J.
      • Kaplan S.
      The incidence of congenital heart disease.
      • Friedman T.
      • Mani A.
      • Elefteriades J.A.
      Bicuspid aortic valve: clinical approach and scientific review of a common clinical entity.
      • Mills P.
      • Leech G.
      • Davies M.
      • Leathan A.
      The natural history of a non-stenotic bicuspid aortic valve.
      • Verma S.
      • Siu S.C.
      Aortic dilatation in patients with bicuspid aortic valve.
      • Sagie A.
      • Vaturi M.
      • Shapira Y.
      [Update in aortic valve diseases].
      • Williams D.S.
      Bicuspid aortic valve.
      Hoffman and Kaplan
      • Hoffman J.
      • Kaplan S.
      The incidence of congenital heart disease.
      report a prevalence in this range based on “unselected consecutive necropsies,” which they consider the “standard” for detection. This makes BAV the most common congenital anomaly affecting the human heart (if one excludes tiny muscular ventricular septal defects that close spontaneously by 1 year of age). It is said that BAV accounts for more morbidity and mortality than all other congenital heart lesions combined.
      • Verma S.
      • Siu S.C.
      Aortic dilatation in patients with bicuspid aortic valve.
      • Ward C.
      Clinical significance of the bicuspid aortic valve.
      This mortality may be incurred via multiple disease mechanisms: aortic stenosis (AS), aortic insufficiency (AI), or ascending aortic aneurysm and dissection. Male patients are thought to predominate, by a margin of approximately 2 to 1.
      • Movahed M.R.
      • Hepner A.D.
      • Ahmadi-Kashani M.
      Echocardiographic prevalence of bicuspid aortic valve in the population.
      It has been shown in a single-center experience that 50% of all aortic valve operations performed on patients aged more than 50 years are done for BAV disease.
      • Roberts W.C.
      • Ko J.M.
      Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation.
      Likewise, 50% of all valve operations performed in patients with coarctation of the aorta can be attributed to BAV disease.
      • Roos-Hesselink J.W.
      • Scholzel B.E.
      • Heijdra R.J.
      • Spitaels S.E.
      • Meijboom F.J.
      • Boersma E.
      • et al.
      Aortic valve and aortic arch pathology after coarctation repair.
      Although these statistics are staggering, the true burden of BAV disease may be grossly underestimated, because it may remain asymptomatic in childhood and even into adulthood, so that no imaging studies are indicated or performed.
      • Brandenburg Jr., R.O.
      • Tajik A.J.
      • Edwards W.D.
      • Reeder G.S.
      • Shub C.
      • Seward J.B.
      Accuracy of 2-dimensional echocardiographic diagnosis of congenitally bicuspid aortic valve: echocardiographic-anatomic correlation in 115 patients.

      II Likelihood of aneurysm development in patients with bicuspid aortic valve disease

      Multiple studies have quantified the risk over time of development of dilatation of the ascending aorta (to a size of 4.0-4.5 cm) in patients with BAV. These studies indicate that 20% to 30% of patients with BAV develop aneurysmal enlargement during a follow-up of 9 to 25 years.
      • Michelena H.I.
      • Desjardins V.A.
      • Avierinos J.F.
      • Russo A.
      • Nkomo V.T.
      • Sundt T.M.
      • et al.
      Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community.
      • Tzemos N.
      • Therrien J.
      • Yip J.
      • Thanassoulis G.
      • Tremblay S.
      • Jamorski M.T.
      • et al.
      Outcomes in adults with bicuspid aortic valves.
      • Michelena H.I.
      • Prakash S.K.
      • Della Corte A.
      • Bissell M.M.
      • Anavekar N.
      • Mathieu P.
      • et al.
      Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon).
      A recent review article suggests that up to 84% of patients with BAV may ultimately develop an aneurysm (based on 8 individual studies). The risk of aneurysm development was found to be 80-fold higher than for the general population.
      • Michelena H.I.
      • Prakash S.K.
      • Della Corte A.
      • Bissell M.M.
      • Anavekar N.
      • Mathieu P.
      • et al.
      Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon).

      III Aneurysm location

      Heterogeneity is the rule in terms of the segment of the ascending aorta involved by bicuspid aneurysm.
      • Michelena H.I.
      • Desjardins V.A.
      • Avierinos J.F.
      • Russo A.
      • Nkomo V.T.
      • Sundt T.M.
      • et al.
      Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community.
      The tubular ascending aorta is most commonly involved (60%-70% of bicuspid aneurysms), although all segments, including the aortic root and the aortic arch, can be involved (Figure 2). There is evidence that the “root phenotype” of BAV aortopathy, in which the predominant dilatation is at the level of the sinuses of Valsalva, represents a more malignant and rapidly progressive aortopathy (Section 3.C).
      • Della Corte A.
      • Bancone C.
      • Buonocore M.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • et al.
      Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve.
      • Girdauskas E.
      • Disha K.
      • Raisin H.H.
      • Secknus M.A.
      • Borger M.A.
      • Kuntze T.
      Risk of late aortic events after an isolated aortic valve replacement for bicuspid aortic valve stenosis with concomitant ascending aortic dilation.
      • Rylski B.
      • Desai N.D.
      • Bavaria J.E.
      • Vallabhajosyula P.
      • Moser W.
      • Pochettino A.
      • et al.
      Aortic valve morphology determines the presentation and surgical approach to acute type A aortic dissection.
      • Etz C.D.
      • von Aspern K.
      • Hoyer A.
      • Girrbach F.F.
      • Leontyev S.
      • Bakhtiary F.
      • et al.
      Acute type A aortic dissection: characteristics and outcomes comparing patients with bicuspid versus tricuspid aortic valve.
      Figure thumbnail gr2
      Figure 2Anatomic distribution of aortic aneurysms in patients with BAV. BAV, Bicuspid aortic valve.
      (Aortic Institute at Yale-New Haven, unpublished data, June 30, 2017.) These data are similar to those reported by Michelena and colleagues.
      • Michelena H.I.
      • Desjardins V.A.
      • Avierinos J.F.
      • Russo A.
      • Nkomo V.T.
      • Sundt T.M.
      • et al.
      Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community.
      The marked heterogeneity of BAV-associated aneurysm location is distinctly different from other common types of ascending aortic aneurysms. Degenerative aneurysms tend to start in the mid-ascending aorta and then progress distally and proximally, whereas those associated with connective tissue disease are usually confined to the aortic root. BAV morphology and pathology seem to play a role in determining where the BAV-associated aneurysm is located (Section 3).

      IV Major role in causation of aortic dissection

      An important point to note is the large number of aortic dissections associated with BAV aortopathy. Although only 5% or less of patients with BAV will have aortic dissection over a lifetime,
      • Ward C.
      Clinical significance of the bicuspid aortic valve.
      BAV disease affects 1 in every 50 to 100 human beings. Thus, not only the better appreciated Marfan syndrome but also BAV is an important cause of aortic dissection.
      • Januzzi J.L.
      • Isselbacher E.M.
      • Fattori R.
      • Cooper J.V.
      • Smith D.E.
      • Fang J.
      • et al.
      Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD).
      However, recent studies have found substantially lower rates of aortic dissection in patients with BAV than previously determined, especially in younger patients.
      • Tzemos N.
      • Therrien J.
      • Yip J.
      • Thanassoulis G.
      • Tremblay S.
      • Jamorski M.T.
      • et al.
      Outcomes in adults with bicuspid aortic valves.
      • Michelena H.I.
      • Khanna A.D.
      • Mahoney D.
      • Margaryan E.
      • Topilsky Y.
      • Suri R.M.
      • et al.
      Incidence of aortic complications in patients with bicuspid aortic valves.
      For instance, in a recent study by Itagaki and colleagues,
      • Itagaki S.
      • Chikwe J.P.
      • Chiang Y.P.
      • Egorova N.N.
      • Adams D.H.
      Long-term risk for aortic complications after aortic valve replacement in patients with bicuspid aortic valve versus Marfan syndrome.
      the rate of aortic dissection in patients with BAV 15 years after aortic valve replacement (AVR) was 0.55% and not significantly different from patients with TAV (0.41%). However, patients with Marfan syndrome had a substantially higher rate of aortic dissection (5.5%) that was significantly greater than the rate in patients with BAV or TAV (P < .001).

      Genetics

      Although there is a definite genetic component to BAV disease, the precise patterns of inheritance have been elusive. Approximately 9% to 15% of first-order family members also have BAV disease, with men and women equally affected within those families.
      • Huntington K.
      • Hunter A.G.
      • Chan K.L.
      A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve.
      • Clementi M.
      • Notari L.
      • Borghi A.
      • Tenconi R.
      Familial congenital bicuspid aortic valve: a disorder of uncertain inheritance.
      • Emanuel R.
      • Withers R.
      • O'Brien K.
      • Ross P.
      • Feizi O.
      Congenitally bicuspid aortic valves. Clinicogenetic study of 41 families.
      These percentages are higher than in the general population (1%-2%), demonstrating the influence of genetics in this disease. Missense mutations in the NOTCH1 gene have been implicated in some patients with BAV disease.
      • McKellar S.H.
      • Tester D.J.
      • Yagubyan M.
      • Majumdar R.
      • Ackerman M.J.
      • Sundt III, T.M.
      Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms.
      • Prakash S.K.
      • Bosse Y.
      • Muehlschlegel J.D.
      • Michelena H.I.
      • Limongelli G.
      • Della Corte A.
      • et al.
      A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium).
      • Garg V.
      • Muth A.N.
      • Ransom J.F.
      • Schluterman M.K.
      • Barnes R.
      • King I.N.
      • et al.
      Mutations in NOTCH1 cause aortic valve disease.
      The vital NOTCH signaling pathway, involved in differentiation of multiple organs (including skeletal muscle, central nervous system, pancreas, and blood vessels), is highly evolutionarily conserved (ie, in humans, mice, and zebrafish).
      • Iso T.
      • Hamamori Y.
      • Kedes L.
      Notch signaling in vascular development.
      High evolutionary conservation indicates critical pathways whose aberration is likely to lead to significant or life-threatening disease. NOTCH genes play an important role in familial bicuspid valve disease, but they are found in only 4% of spontaneous cases.
      • Mohamed S.A.
      • Aherrahrou Z.
      • Liptau H.
      • Erasmi A.W.
      • Hagemann C.
      • Wrobel S.
      • et al.
      Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve.
      The variety and complexity of inheritance of BAV are under intense investigation but remain to be fully clarified.

      VI Associated lesions

      Many other lesions and syndromes are strongly associated with BAV (Table 1). Associated anatomic lesions include aortic coarctation and patent ductus arteriosus. Coarctation-mediated hypertension greatly increases the risk of aortic dissection.
      • Warnes C.A.
      Bicuspid aortic valve and coarctation: two villains part of a diffuse problem.
      In the presurgical era, death from aortic dissection occurred in 19% of patients with BAV, but in 50% of patients with concomitant BAV disease and coarctation.
      • Abbott M.
      Coarctation of the aorta of adult-type.
      • Braverman A.C.
      • Guven H.
      • Beardslee M.A.
      • Makan M.
      • Kates A.M.
      • Moon M.R.
      The bicuspid aortic valve.
      Aortic coarctation accompanies BAV more commonly in men (4:1) than in women.
      • Warnes C.A.
      Bicuspid aortic valve and coarctation: two villains part of a diffuse problem.
      Syndromes associated with BAV disease include Turner's syndrome (monosomy X, characterized by short stature, lymphedema of the hands and feet, and amenorrhea) and William's syndrome (abnormal facial appearance, low nasal bridge, unusually cheerful demeanor). In addition to those lesions described in Table 1, patients with BAV are also known to have an increased prevalence of anterior mitral valve leaflet elongation and prolapse.
      • Lad V.
      • David T.E.
      • Vegas A.
      Mitral regurgitation due to myxomatous degeneration combined with bicuspid aortic valve disease is often due to prolapse of the anterior leaflet of the mitral valve.
      • Charitos E.I.
      • Hanke T.
      • Karluss A.
      • Hilker L.
      • Stierle U.
      • Sievers H.H.
      New insights into bicuspid aortic valve disease: the elongated anterior mitral leaflet.
      Table 1Cardiovascular conditions associated with bicuspid aortic valve disease
      Modification of Braverman A. BAV and associated conditions. Graphic 83657, version 1.0. In: Up-to-Date. Alphen aan den Rijn, The Netherlands: Wolters Kluwer; 2016. Available at: http://www.uptodate.com. Accessed June 30, 2017.
      ConditionIncidence of BAV
      Coarctation of the aorta50%
      Turner syndrome30%
      Supravalvular AS30%
      Sinus of Valsalva aneurysm15%-20%
      Ventricular septal defect30%
      Shone complex60%-85%
      Ascending aortic aneurysmCommon
      Loeys–Dietz syndrome2.5%-17%
      ACTA2 mutation familial thoracic aneurysm syndrome3%
      Anterior mitral leaflet prolongation/prolapseCommon
      • Lad V.
      • David T.E.
      • Vegas A.
      Mitral regurgitation due to myxomatous degeneration combined with bicuspid aortic valve disease is often due to prolapse of the anterior leaflet of the mitral valve.
      • Charitos E.I.
      • Hanke T.
      • Karluss A.
      • Hilker L.
      • Stierle U.
      • Sievers H.H.
      New insights into bicuspid aortic valve disease: the elongated anterior mitral leaflet.
      BAV, Bicuspid aortic valve; AS, aortic stenosis.

      Natural History

      BAV disease can cause morbidity and mortality through the valve disease (stenosis or insufficiency) or by ascending aortic aneurysm (leading to aortic dissection or, in rare cases, rupture). However, recent studies have demonstrated, in the modern era of diagnosis and care, an overall survival for patients with BAV identical to that of the normal population.
      • Michelena H.I.
      • Desjardins V.A.
      • Avierinos J.F.
      • Russo A.
      • Nkomo V.T.
      • Sundt T.M.
      • et al.
      Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community.
      As long as patients are followed regularly and surgery is offered in a timely fashion, then the risk of catastrophic aortic events is low. However, some important observations should be kept in mind when following patients with BAV.

      Aortic valve dysfunction is not needed for aortic dissection to occur

      It is important to recognize that neither AS nor AI needs to be present for aortic dissection to occur.
      • Hahn R.T.
      • Roman M.J.
      • Mogtader A.H.
      • Devereux R.B.
      Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves.
      In BAV disease, valvular complications—AS or regurgitation—progress at their own independent rates, different from the rate of progression of the bicuspid aneurysm. Thus, the lack of AS does not preclude aortic dissection from occurring. However, patients with BAV and valvular disease (stenosis or insufficiency) are at increased risk of rupture and dissection of the aorta.
      • Keane M.G.
      • Wiegers S.E.
      • Plappert T.
      • Pochettino A.
      • Bavaria J.E.
      • Sutton M.G.
      Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions.
      Evidence increasingly demonstrates regurgitant BAVs having a more malignant phenotype than stenotic BAVs, with a higher risk of aortic dissection.
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Espinoza A.
      • Misfeld M.
      • Borger M.A.
      • et al.
      Aortic dissection after previous aortic valve replacement for bicuspid aortic valve disease.
      This topic will be discussed in more detail in Sections 3 and 6.

      II More malignant behavior of bicuspid aorta?

      Many have thought of BAV aortopathy as “Marfan syndrome light”—that is, more severe than ordinary aortic aneurysm disease, but not quite as virulent as the Marfanoid aorta. Despite the clinical impression that BAV aortopathy is a malignant actor, supportive concrete evidence has been elusive.
      A study by Davies and colleagues
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      looked for disparities in behavior between patients with ascending aortic aneurysm with and without BAV disease. Patients with BAV disease presented at a smaller aortic diameter (4.6 vs 4.9 cm for patients without BAV). Also, their aortas grew more rapidly than those of patients with TAV: 1.9 mm/year compared with 1.3 mm/year.
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      A higher proportion of patients with BAV required operative treatment of their aortas (72.8% vs 44.8%) at a significantly younger age (48.9 vs 63.1 years).
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      However, among unoperated patients, there was no detriment in survival for the bicuspid group, who actually did better than the TAV group (8.6% vs 25.7% rate of rupture, dissection, or death at 5 years of follow-up).
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      This likely reflects the substantially younger age at presentation of the bicuspid group (49 vs 64 years).
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      However, in the BAV group, those patients with AS in addition to the aneurysm had an increased risk of aortic rupture, dissection, or death before operative repair when compared with patients with a normally functioning bicuspid valve.
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      One possible limitation of these data is the fact that they are derived from a thoracic aortic referral center, and therefore may not accurately reflect the natural history of BAV aneurysms in the general population.
      Other studies have also reported “mild” behavior with near normal long-term survival and low overall growth rates for the bicuspid aorta, on the order of 0.4 to 0.6 mm/year, with no differences noted according to specific pattern of leaflet fusion.
      • Della Corte A.
      • Bancone C.
      • Buonocore M.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • et al.
      Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve.
      • Detaint D.
      • Michelena H.I.
      • Nkomo V.T.
      • Vahanian A.
      • Jondeau G.
      • Sarano M.E.
      Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy.
      These studies did not find a relationship between growth rate and original aortic size. The discrepancies between these studies and the study by Davies and colleagues
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      have several possible explanations. First, these were studies derived from echocardiographic databases and not from a thoracic aortic referral center, which may have implications on patient selection bias. Second, the investigators may not have adequately imaged the uppermost portion of the ascending aorta in some patients, because this is a known limitation of echocardiography. Finally, the patients from the echocardiographic-based studies initially presented with smaller aortic diameters (4.1 and 3.8 cm) than those in the study by Davies and colleagues
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      (4.6 cm).

      III Medical therapy for bicuspid aortopathy?

      It is unclear whether any medical therapy is effective in preventing adverse events in aortic aneurysms of any kind, even in the most thoroughly studied Marfan population. Although beta-blockers and angiotensin receptor blocking drugs are commonly applied to “protect” the BAV, supportive evidence is lacking.
      • Chun A.S.
      • Elefteriades J.A.
      • Mukherjee S.K.
      Medical treatment for thoracic aortic aneurysm - much more work to be done.
      • Danyi P.
      • Elefteriades J.A.
      • Jovin I.S.
      Medical therapy of thoracic aortic aneurysms: are we there yet?.
      • Ziganshin B.A.
      • Mukherjee S.K.
      • Elefteriades J.A.
      Atenolol versus Losartan in Marfan's Syndrome.
      However, such agents should be given to patients with documented hypertension. Statins have been shown to be ineffective, whereas other studies show a possible protective effect.
      • Regeer M.V.
      • van Rosendael P.J.
      • Kamperidis V.
      • Schalij M.J.
      • Bax J.J.
      • Marsan N.A.
      • et al.
      Effect of statins on aortic root growth rate in patients with bicuspid aortic valve anatomy.

      IV Contemporary clinical outcomes

      Contemporary clinical outcomes for patients with BAV have been summarized in a comprehensive table by Michelena and colleagues
      • Michelena H.I.
      • Prakash S.K.
      • Della Corte A.
      • Bissell M.M.
      • Anavekar N.
      • Mathieu P.
      • et al.
      Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon).
      from the International BAV Consortium (Table 2). Age at presentation, survival, and likelihood of heart failure, aortic valve surgery, endocarditis, aneurysm formation, aneurysm surgery, and aortic dissection are described for 8 contemporary clinical studies. Table 2 demonstrates excellent overall survival of patients with BAV in community, population-based studies, whereas outcomes are poorer in referral center patients who have required AVR. Heart failure is particularly uncommon in patients with BAV, and AS is a more common indication for surgery than AI. Aneurysm formation (aortic diameter >45 mm) occurs in 25% to 45% of patients over prolonged periods of follow-up, but aortic dissection is a rare event (∼1%) outside of tertiary referral center populations, where it is more common (∼10%).
      • Michelena H.I.
      • Prakash S.K.
      • Della Corte A.
      • Bissell M.M.
      • Anavekar N.
      • Mathieu P.
      • et al.
      Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon).
      Table 2Contemporary clinical outcomes in patients with bicuspid aortic valve disease
      Reproduced with permission from Michelena and colleagues.
      • Michelena H.I.
      • Prakash S.K.
      • Della Corte A.
      • Bissell M.M.
      • Anavekar N.
      • Mathieu P.
      • et al.
      Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon).
      Study features, clinical outcomesContemporary clinical outcomes of BAV studies
      Outcomes reported as percentage only were not reported within Kaplan–Meier survival analyses. Survival in the first 3 studies26,27,33 was not different than that of the general population. Survival in the study by McKellar and colleagues58 was inferior to that of the general population, and the rest of the studies were not compared with the general population.
      Michelena and colleagues
      • Michelena H.I.
      • Desjardins V.A.
      • Avierinos J.F.
      • Russo A.
      • Nkomo V.T.
      • Sundt T.M.
      • et al.
      Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community.
      Tzemos and colleagues
      • Tzemos N.
      • Therrien J.
      • Yip J.
      • Thanassoulis G.
      • Tremblay S.
      • Jamorski M.T.
      • et al.
      Outcomes in adults with bicuspid aortic valves.
      Michelena and colleagues
      • Michelena H.I.
      • Khanna A.D.
      • Mahoney D.
      • Margaryan E.
      • Topilsky Y.
      • Suri R.M.
      • et al.
      Incidence of aortic complications in patients with bicuspid aortic valves.
      Davies and colleagues
      • Davies R.R.
      • Kaple R.K.
      • Mandapati D.
      • Gallo A.
      • Botta Jr., D.M.
      • Elefteriades J.A.
      • et al.
      Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve.
      ,
      This study compared patients with BAV with aneurysms versus patients with TAV with aneurysms. The incidence of aortic dissection was the same for both groups with superior survival in patients with BAV and both groups with dissection at similar aortic diameters.
      Russo and colleagues
      • Russo C.F.
      • Mazzetti S.
      • Garatti A.
      • Ribera E.
      • Milazzo A.
      • Bruschi G.
      • et al.
      Aortic complications after bicuspid aortic valve replacement: long-term results.
      Borger and colleagues
      • Borger M.A.
      • Preston M.
      • Ivanov J.
      • Fedak P.W.
      • Davierwala P.
      • Armstrong S.
      • et al.
      Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease?.
      ,
      This study suggested that patients with aortic dimension 45 mm or greater at the time of AVR should have the aorta concomitantly repaired, the basis of the current recommendations.
      McKellar and colleagues
      • McKellar S.H.
      • Michelena H.I.
      • Li Z.
      • Schaff H.V.
      • Sundt III, T.M.
      Long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves.
      Girdauskas and colleagues
      • Girdauskas E.
      • Disha K.
      • Raisin H.H.
      • Secknus M.A.
      • Borger M.A.
      • Kuntze T.
      Risk of late aortic events after an isolated aortic valve replacement for bicuspid aortic valve stenosis with concomitant ascending aortic dilation.
      ,
      This study included consecutive patients with isolated AVR performed for AS only. However, 21 patients with predominant dilatation of the root (mean diameter, 44 mm) and severe aortic regurgitation who underwent AVR were followed in parallel for a mean of 10 years, and 2 acute dissections occurred.
      Publication year20082008201120072002200420102012
      Clinical settingCommunity, population-basedTertiary referral centerCommunity, population-basedTertiary referral center`Tertiary referral centerTertiary referral centerTertiary referral centerTertiary referral center
      Inclusion characteristicsMinimal BAV dysfunctionAny BAV dysfunctionAny BAV dysfunctionAny BAV dysfunction with aortic aneurysm (mean baseline diameter 4.6 mm)Status post-AVRStatus post-AVRStatus post-AVRStatus postisolated AVR with aortic aneurysm (mean baseline diameter 4.6 mm)
      N21264241670502011286153
      Baseline age, y, mean ± SD32 ± 2035 ± 1635 ± 214951 ± 1256 ± 1558 ± 1454 ± 11
      Follow-up y, mean ± SD15 ± 69 ± 516 ± 7520 ± 210 ± 412 ± 712 ± 3
      Survival90% at 20 y96% at 10 y80% at 25 y91% at 5 y≈40% at 15 y67% at 15 y52% at 15 y78% at 15 y
      Heart failure7% at 20 y2%
      Aortic valve surgery24% at 20 y21%53% at 25 y68%
      Reason for aortic valve surgeryAS 67%

      AR 15%
      AS 61%

      AR 27%
      AS 61%

      AR 29%
      Endocarditis2%2%2%4%2%
      Aneurysm formation (definition, mm)39% (>40 mm)45% (>35 mm)26% at 25 y (≥45 mm)9% (≥50 mm)10% (≥50 mm)3% (≥50 mm)
      Aortic surgery (for aneurysm)5% at 20 y7%9%73%6%9%1%3%
      Aortic dissection0% at 20 y1%0.5% at 25 y9%10% at 20 y0.5%1% at 15 y0%
      BAV, Bicuspid aortic valve; AVR, aortic valve replacement; SD, standard deviation; AS, aortic stenosis; AR, aortic regurgitation.
      Outcomes reported as percentage only were not reported within Kaplan–Meier survival analyses. Survival in the first 3 studies
      • Michelena H.I.
      • Desjardins V.A.
      • Avierinos J.F.
      • Russo A.
      • Nkomo V.T.
      • Sundt T.M.
      • et al.
      Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community.
      • Tzemos N.
      • Therrien J.
      • Yip J.
      • Thanassoulis G.
      • Tremblay S.
      • Jamorski M.T.
      • et al.
      Outcomes in adults with bicuspid aortic valves.
      • Michelena H.I.
      • Khanna A.D.
      • Mahoney D.
      • Margaryan E.
      • Topilsky Y.
      • Suri R.M.
      • et al.
      Incidence of aortic complications in patients with bicuspid aortic valves.
      was not different than that of the general population. Survival in the study by McKellar and colleagues
      • McKellar S.H.
      • Michelena H.I.
      • Li Z.
      • Schaff H.V.
      • Sundt III, T.M.
      Long-term risk of aortic events following aortic valve replacement in patients with bicuspid aortic valves.
      was inferior to that of the general population, and the rest of the studies were not compared with the general population.
      This study compared patients with BAV with aneurysms versus patients with TAV with aneurysms. The incidence of aortic dissection was the same for both groups with superior survival in patients with BAV and both groups with dissection at similar aortic diameters.
      This study suggested that patients with aortic dimension 45 mm or greater at the time of AVR should have the aorta concomitantly repaired, the basis of the current recommendations.
      § This study included consecutive patients with isolated AVR performed for AS only. However, 21 patients with predominant dilatation of the root (mean diameter, 44 mm) and severe aortic regurgitation who underwent AVR were followed in parallel for a mean of 10 years, and 2 acute dissections occurred.

      3. Patient Phenotypes

      Introduction

      Evidence of phenotypic heterogeneity of BAV aortopathy has emerged in the last decade from several observational studies and stimulated a critical reappraisal of literature and treatment recommendations. The hypothesis has been proposed that different types of BAV aortopathy (ie, so-called aortic phenotypes) may be caused by distinct pathogenetic mechanisms and therefore require individualized surgical approaches.
      • Fedak P.W.
      • Verma S.
      Bicuspid aortopathy and the development of individualized resection strategies.
      • Della Corte A.
      Phenotypic heterogeneity of bicuspid aortopathy: a potential key to decode the prognosis?.
      In particular, the 2 long-debated theories on BAV aortopathy pathogenesis, namely, the genetic and the hemodynamic theories, could both be plausible inasmuch as different phenotypic forms might be subtended by different contributions of both causative factors. Phenotypic heterogeneity of BAV aortopathy also may explain to some extent the inconsistencies in published natural history and follow-up studies, especially regarding the risk of aortic events in BAV disease. Previous data from mixed BAV cohorts resulted in a broad spectrum of surgical treatment methods being suggested, ranging from very conservative approaches to very aggressive recommendations, usually extrapolated from guidelines for management of patients with connective tissue disorders (eg, Marfan syndrome).
      • Hiratzka L.F.
      • Bakris G.L.
      • Beckman J.A.
      • Bersin R.M.
      • Carr V.F.
      • Casey Jr., D.E.
      • et al.
      2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
      Although the evidence of BAV aortopathy heterogeneity has gained increasing recognition in the last decade, data on individual aortic phenotypes are still scarce. The majority of published natural history/follow-up studies contain mixed BAV cohorts and include different stages of BAV disease. A better understanding of the interaction among morphologic features, functional characteristics of the aortic root, and transvalvular hemodynamics is required.
      Scientific efforts to address the phenotypic heterogeneity in BAV aortopathy were mainly based on valve-related factors, including BAV morphology (ie, number and location of fused cusps), functional lesion (ie, stenosis, insufficiency or mixed lesions), and shape/configuration of the proximal aorta, which are addressed in detail next.

      Bicuspid Aortic Valve Morphology

      As mentioned in the Introduction, BAV morphology is described throughout this article according to the classification of Sievers and Schmidtke
      • Sievers H.H.
      • Schmidtke C.
      A classification system for the bicuspid aortic valve from 304 surgical specimens.
      (Figure 1). BAV morphology with fusion of the right-left coronary cusps (ie, Sievers type I, R/L) and right noncoronary cusp (Sievers type I, R/N) represents the 2 most common BAV morphologies, accounting for approximately 75% and 20% of clinical cases, respectively.
      • Sievers H.H.
      • Schmidtke C.
      A classification system for the bicuspid aortic valve from 304 surgical specimens.
      Sievers type I L/N and patients without a raphe (ie, Sievers type 0) are uncommon. The low prevalence of these specific fusion morphologies resulted in exclusion of these patients in most case series.
      An embryogenetic study by Fernandez and colleagues
      • Fernandez B.
      • Duran A.C.
      • Fernandez-Gallego T.
      • Fernandez M.C.
      • Such M.
      • Arque J.M.
      • et al.
      Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities.
      demonstrated that the 2 most common BAV morphologies (ie, R/L and R/N) develop at different embryonic stages through distinct mechanisms and therefore should be interpreted as separate etiologic entities. The authors further suggested that the etiological factors giving rise to the specific BAV morphologies might be involved in the occurrence of distinct forms of BAV aortopathy.
      • Fernandez B.
      • Duran A.C.
      • Fernandez-Gallego T.
      • Fernandez M.C.
      • Such M.
      • Arque J.M.
      • et al.
      Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities.
      However, it is known that both morphologies can frequently appear within the same pedigree.
      • Robledo-Carmona J.
      • Rodriguez-Bailon I.
      • Carrasco-Chinchilla F.
      • Fernandez B.
      • Jimenez-Navarro M.
      • Porras-Martin C.
      • et al.
      Hereditary patterns of bicuspid aortic valve in a hundred families.
      Recent 4-dimensional (4D) flow magnetic resonance imaging (MRI) studies demonstrated that distinct aortic cusp fusion patterns result in specific orientations of eccentric flow jets (Figure 3),
      • Bissell M.M.
      • Hess A.T.
      • Biasiolli L.
      • Glaze S.J.
      • Loudon M.
      • Pitcher A.
      • et al.
      Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.
      • Guzzardi D.G.
      • Barker A.J.
      • van Ooij P.
      • Malaisrie S.C.
      • Puthumana J.J.
      • Belke D.D.
      • et al.
      Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      which in turn may lead to differential distributions of aortic wall shear stress (WSS)
      • Bissell M.M.
      • Hess A.T.
      • Biasiolli L.
      • Glaze S.J.
      • Loudon M.
      • Pitcher A.
      • et al.
      Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      and subsequent focal flow-induced vascular remodeling.
      • Guzzardi D.G.
      • Barker A.J.
      • van Ooij P.
      • Malaisrie S.C.
      • Puthumana J.J.
      • Belke D.D.
      • et al.
      Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.
      Eccentric transvalvular flow results in elevated regional WSS at the right-anterior wall of the proximal aorta for R/L BAV and right-posterior walls for R/N BAV.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      Bissell and colleagues
      • Bissell M.M.
      • Hess A.T.
      • Biasiolli L.
      • Glaze S.J.
      • Loudon M.
      • Pitcher A.
      • et al.
      Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.
      demonstrated more severe flow abnormalities (complex flow, higher in-plane WSS) and larger aortas in the R/N BAV versus R/L BAV. However, propagation patterns of transvalvular flow are still not uniform in patients with BAV with the same cusp fusion morphology,
      • Bissell M.M.
      • Hess A.T.
      • Biasiolli L.
      • Glaze S.J.
      • Loudon M.
      • Pitcher A.
      • et al.
      Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.
      • Guzzardi D.G.
      • Barker A.J.
      • van Ooij P.
      • Malaisrie S.C.
      • Puthumana J.J.
      • Belke D.D.
      • et al.
      Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Scholle T.
      • Fey B.
      • Theis B.
      • et al.
      Correlation between systolic transvalvular flow and proximal aortic wall changes in bicuspid aortic valve stenosis.
      and thus the impact of additional functional parameters (eg, subvalvular components, geometric orientation of residual aortic valve orifice) has been postulated.
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Scholle T.
      • Fey B.
      • Theis B.
      • et al.
      Correlation between systolic transvalvular flow and proximal aortic wall changes in bicuspid aortic valve stenosis.
      Figure thumbnail gr3
      Figure 3A, Normal aortic valve anatomy with an opening angle of 75 degrees, flow jet angle (θ1, which measures displacement of peak systolic flow [arrow] from vessel midline). B, BAV showing restricted valve opening (opening angle of 60 degrees), displaced flow jet with associated θ1, displaced high-flow velocities near the vessel wall leading to asymmetrically increased WSS at the aortic convexity. WSS, Wall shear stress.
      Reproduced with permission from Burris and Hope.
      • Burris N.S.
      • Hope M.D.
      4D flow MRI applications for aortic disease.
      The R/L morphology has been associated with younger patient age and absence of significant AS or regurgitation,
      • Sievers H.H.
      • Stierle U.
      • Hachmann R.M.
      • Charitos E.I.
      New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics.
      whereas a greater prevalence of female patients is observed in those with R/N.
      • Schaefer B.
      • Lewin M.
      • Stout K.
      • Gill E.
      • Prueitt A.
      • Byers P.
      • et al.
      The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.
      • Della Corte A.
      • Bancone C.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • D'Oria V.
      • et al.
      Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation.
      Regarding the associated aortopathy, BAV R/L fusion morphology has been linked with increased diameters of the sinuses of Valsalva.
      • Detaint D.
      • Michelena H.I.
      • Nkomo V.T.
      • Vahanian A.
      • Jondeau G.
      • Sarano M.E.
      Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy.
      • Schaefer B.
      • Lewin M.
      • Stout K.
      • Gill E.
      • Prueitt A.
      • Byers P.
      • et al.
      The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.
      • Della Corte A.
      • Bancone C.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • D'Oria V.
      • et al.
      Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation.
      • Merritt B.A.
      • Turin A.
      • Markl M.
      • Malaisrie S.C.
      • McCarthy P.M.
      • Carr J.C.
      Association between leaflet fusion pattern and thoracic aorta morphology in patients with bicuspid aortic valve.
      • Page M.
      • Mongeon F.P.
      • Stevens L.M.
      • Souliere V.
      • Khairy P.
      • El-Hamamsy I.
      Aortic dilation rates in patients with bicuspid aortic valve: correlations with cusp fusion phenotype.
      In contrast, R/N fusion morphology is associated with a smaller dimension of the aortic root and larger aortic arch diameters.
      • Schaefer B.
      • Lewin M.
      • Stout K.
      • Gill E.
      • Prueitt A.
      • Byers P.
      • et al.
      The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.
      • Della Corte A.
      • Bancone C.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • D'Oria V.
      • et al.
      Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation.
      • Merritt B.A.
      • Turin A.
      • Markl M.
      • Malaisrie S.C.
      • McCarthy P.M.
      • Carr J.C.
      Association between leaflet fusion pattern and thoracic aorta morphology in patients with bicuspid aortic valve.
      • Page M.
      • Mongeon F.P.
      • Stevens L.M.
      • Souliere V.
      • Khairy P.
      • El-Hamamsy I.
      Aortic dilation rates in patients with bicuspid aortic valve: correlations with cusp fusion phenotype.
      However, some authors found no significant correlation between aortic dimensions and BAV morphology.
      • Buchner S.
      • Hulsmann M.
      • Poschenrieder F.
      • Hamer O.W.
      • Fellner C.
      • Kobuch R.
      • et al.
      Variable phenotypes of bicuspid aortic valve disease: classification by cardiovascular magnetic resonance.
      • Cecconi M.
      • Manfrin M.
      • Moraca A.
      • Zanoli R.
      • Colonna P.L.
      • Bettuzzi M.G.
      • et al.
      Aortic dimensions in patients with bicuspid aortic valve without significant valve dysfunction.
      In addition, the published data on progression of BAV aortopathy in R/L versus R/N fusion morphologies are inconsistent. Some authors found that patients with BAV with R/L fusion are at increased risk of rapid aortic dilatation,
      • Page M.
      • Mongeon F.P.
      • Stevens L.M.
      • Souliere V.
      • Khairy P.
      • El-Hamamsy I.
      Aortic dilation rates in patients with bicuspid aortic valve: correlations with cusp fusion phenotype.
      • Thanassoulis G.
      • Yip J.W.
      • Filion K.
      • Jamorski M.
      • Webb G.
      • Siu S.C.
      • et al.
      Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves.
      whereas others reported the same findings in patients with R/N fusion.
      • Holmes K.W.
      • Lehmann C.U.
      • Dalal D.
      • Nasir K.
      • Dietz H.C.
      • Ravekes W.J.
      • et al.
      Progressive dilation of the ascending aorta in children with isolated bicuspid aortic valve.
      Different statistical approaches and different age ranges of the study populations may explain the differences between studies, because the 2 types of BAV morphology seem to progress in an age-dependent manner.
      • Della Corte A.
      • Bancone C.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • D'Oria V.
      • et al.
      Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation.
      • Fernandes S.M.
      • Khairy P.
      • Sanders S.P.
      • Colan S.D.
      Bicuspid aortic valve morphology and interventions in the young.
      Other studies have found no correlation between ascending aortic dilatation rates and BAV morphology.
      • Della Corte A.
      • Bancone C.
      • Buonocore M.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • et al.
      Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve.
      • Detaint D.
      • Michelena H.I.
      • Nkomo V.T.
      • Vahanian A.
      • Jondeau G.
      • Sarano M.E.
      Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy.
      The data on proximal aortopathy in unicuspid aortic valve (UAV) disease are limited. Sievers and colleagues
      • Sievers H.H.
      • Stierle U.
      • Mohamed S.A.
      • Hanke T.
      • Richardt D.
      • Schmidtke C.
      • et al.
      Toward individualized management of the ascending aorta in bicuspid aortic valve surgery: the role of valve phenotype in 1362 patients.
      reported on more extensive aortopathy, including aortic root and ascending aorta, at a very young age in patients with UAV disease. Moreover, patients with UAV disease are more likely to require ascending aortic repair during their valvular procedure.
      • Sievers H.H.
      • Stierle U.
      • Hachmann R.M.
      • Charitos E.I.
      New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics.
      Furthermore, significantly higher expression of GATA5 and endothelial nitric oxide synthase in the ascending aortas of patients with UAV disease versus BAV and TAV disease has been recently reported.
      • Henn D.
      • Perttunen H.
      • Gauer S.
      • Schmied W.
      • Porras C.
      • Such M.
      • et al.
      GATA5 and endothelial nitric oxide synthase expression in the ascending aorta is related to aortic size and valve morphology.
      Another recent study
      • Zhu Y.
      • Roselli E.E.
      • Idrees J.J.
      • Wojnarski C.M.
      • Griffin B.
      • Kalahasti V.
      • et al.
      Outcomes after operations for unicuspid aortic valve with or without ascending repair in adults.
      demonstrated decreased long-term survival in patients with UAV undergoing isolated AVR when compared with patients with UAV who underwent simultaneous aortic surgery.

      Valve Function

      The most common clinical presentation of BAV disease is calcific AS (BAV-AS), usually presenting between the fifth and seventh decades of life in both male and female patients. In contrast, pure/predominant BAV AI (BAV-AI) tends to occur in younger male patients and accounts for only 10% to 15% cases of BAV lesions in autopsy series.
      • Sabet H.Y.
      • Edwards W.D.
      • Tazelaar H.D.
      • Daly R.C.
      Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2,715 additional cases.
      Distinct patterns of associated aortopathy have been observed in BAV-AS versus BAV-AI.
      • Hahn R.T.
      • Roman M.J.
      • Mogtader A.H.
      • Devereux R.B.
      Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves.
      • Sievers H.H.
      • Stierle U.
      • Hachmann R.M.
      • Charitos E.I.
      New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics.
      • Della Corte A.
      • Bancone C.
      • Quarto C.
      • Dialetto G.
      • Covino F.E.
      • Scardone M.
      • et al.
      Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression.
      Moreover, differences in histologic and extracellular matrix (ECM) protein changes,
      • Roberts W.C.
      • Vowels T.J.
      • Ko J.M.
      • Filardo G.
      • Hebeler Jr., R.F.
      • Henry A.C.
      • et al.
      Comparison of the structure of the aortic valve and ascending aorta in adults having aortic valve replacement for aortic stenosis versus for pure aortic regurgitation and resection of the ascending aorta for aneurysm.
      • Girdauskas E.
      • Rouman M.
      • Borger M.A.
      • Kuntze T.
      Comparison of aortic media changes in patients with bicuspid aortic valve stenosis versus bicuspid valve insufficiency and proximal aortic aneurysm.
      • Cotrufo M.
      • Della Corte A.
      • De Santo L.S.
      • Quarto C.
      • De Feo M.
      • Romano G.
      • et al.
      Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results.
      consistent with the clinical evidence from post-AVR follow-up studies,
      • Girdauskas E.
      • Disha K.
      • Secknus M.
      • Borger M.
      • Kuntze T.
      Increased risk of late aortic events after isolated aortic valve replacement in patients with bicuspid aortic valve insufficiency versus stenosis.
      have also led investigators to suggest different pathobiological mechanisms of BAV aortopathy for these 2 groups of patients. BAV-AS is strongly associated with an asymmetric dilatation of the tubular ascending aorta, which represents the most common aortic phenotype.
      • Hahn R.T.
      • Roman M.J.
      • Mogtader A.H.
      • Devereux R.B.
      Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves.
      • Sievers H.H.
      • Stierle U.
      • Hachmann R.M.
      • Charitos E.I.
      New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics.
      • Della Corte A.
      • Bancone C.
      • Quarto C.
      • Dialetto G.
      • Covino F.E.
      • Scardone M.
      • et al.
      Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression.
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Espinoza A.
      • Dubslaff G.
      • Fey B.
      • et al.
      Aortopathy in patients with bicuspid aortic valve stenosis: role of aortic root functional parameters.
      In contrast, BAV-AI is mainly accompanied by aortic root dilatation (ie, so-called root phenotype).
      • Sievers H.H.
      • Stierle U.
      • Hachmann R.M.
      • Charitos E.I.
      New insights in the association between bicuspid aortic valve phenotype, aortic configuration and valve haemodynamics.
      • Della Corte A.
      • Bancone C.
      • Quarto C.
      • Dialetto G.
      • Covino F.E.
      • Scardone M.
      • et al.
      Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression.
      • Girdauskas E.
      • Disha K.
      • Secknus M.
      • Borger M.
      • Kuntze T.
      Increased risk of late aortic events after isolated aortic valve replacement in patients with bicuspid aortic valve insufficiency versus stenosis.
      However, these associations are not absolute, and heterogeneity within subgroups of valve function has been observed.
      • Keane M.G.
      • Wiegers S.E.
      • Plappert T.
      • Pochettino A.
      • Bavaria J.E.
      • Sutton M.G.
      Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions.
      • Della Corte A.
      • Bancone C.
      • Quarto C.
      • Dialetto G.
      • Covino F.E.
      • Scardone M.
      • et al.
      Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression.
      As stated previously, BAV aortopathy is a heterogeneous disease.
      Aortic dilation observed in patients with normally functioning BAVs has been previously used as an argument for a genetic origin of BAV aortopathy.
      • Keane M.G.
      • Wiegers S.E.
      • Plappert T.
      • Pochettino A.
      • Bavaria J.E.
      • Sutton M.G.
      Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions.
      However, recent experimental in vitro models
      • Robicsek F.
      • Thubrikar M.J.
      • Cook J.W.
      • Fowler B.
      The congenitally bicuspid aortic valve: how does it function? Why does it fail?.
      and in vivo 4D flow MRI studies
      • Hope M.D.
      • Hope T.A.
      • Meadows A.K.
      • Ordovas K.G.
      • Urbania T.H.
      • Alley M.T.
      • et al.
      Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns.
      demonstrate that even clinically normally functioning BAVs (ie, without transvalvular pressure gradient or significant insufficiency) are associated with eccentric transvalvular flow and asymmetrically increased WSS in the proximal aorta. Aortic dilatation in normally functioning BAVs occurs most frequently in the tubular ascending aorta
      • La Canna G.
      • Ficarra E.
      • Tsagalau E.
      • Nardi M.
      • Morandini A.
      • Chieffo A.
      • et al.
      Progression rate of ascending aortic dilation in patients with normally functioning bicuspid and tricuspid aortic valves.
      and has a natural history that is comparable to their TAV counterparts in terms of rate of dilatation and occurrence of aortic events.
      • La Canna G.
      • Ficarra E.
      • Tsagalau E.
      • Nardi M.
      • Morandini A.
      • Chieffo A.
      • et al.
      Progression rate of ascending aortic dilation in patients with normally functioning bicuspid and tricuspid aortic valves.

      Shape of the Proximal Aorta

      Della Corte and co-authors
      • Della Corte A.
      • Bancone C.
      • Quarto C.
      • Dialetto G.
      • Covino F.E.
      • Scardone M.
      • et al.
      Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression.
      were the first to introduce a phenotypic classification of the proximal aorta based on the aortic segment involved and suggested the terms “root phenotype” and “ascending phenotype” (Figure 4). This classification system separated patients with BAV with a possible greater expression of genetically triggered aortopathy (ie, root phenotype) from those with a presumed hemodynamic cause of aortopathy (ie, ascending phenotype). Other classification systems for the pattern of dimensions of the different aortic segments have been proposed: Each of them has merits and flaws, and none can completely cover the entire spectrum of forms of dilatation.
      Figure thumbnail gr4
      Figure 4Root phenotype versus ascending phenotype of BAV aortopathy. Echocardiographic imaging is shown in the upper left corner, 3-dimensional reconstruction is shown in lower left corner, and intraoperative findings are shown at right. In the root phenotype, the diameter of the aorta at the level of the sinuses of Valsalva is greater than that of the tubular ascending aorta, whereas in the ascending phenotype the diameter of the tubular ascending aorta is greater than that of the sinuses.
      Four distinct patterns of aortic dilatation in patients with BAV have been suggested by Fazel and coauthors
      • Fazel S.S.
      • Mallidi H.R.
      • Lee R.S.
      • Sheehan M.P.
      • Liang D.
      • Fleischman D.
      • et al.
      The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch.
      from Stanford using a model of hierarchical clustering and integrating nonechocardiographic imaging (ie, computed tomography [CT] scan and MRI). They identified 4 “clusters”: aortic root dilatation alone (cluster I), tubular ascending aorta dilatation alone (cluster II), simultaneous involvement of the tubular portion and aortic arch (cluster III), and more diffuse dilatation involving the aortic root, tubular portion, and aortic arch (cluster IV).
      • Fazel S.S.
      • Mallidi H.R.
      • Lee R.S.
      • Sheehan M.P.
      • Liang D.
      • Fleischman D.
      • et al.
      The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch.
      Cluster IV was the most frequent pattern of aortopathy; however, no risk factor analysis or longitudinal data were included. A slightly modified CT scan–based classification system of proximal aortic shape has been used by Kang and co-authors,
      • Kang J.W.
      • Song H.G.
      • Yang D.H.
      • Baek S.
      • Kim D.H.
      • Song J.M.
      • et al.
      Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction and bicuspid aortopathy: comprehensive evaluation using MDCT and echocardiography.
      confirming the previously reported association of the atypical morphologies (mainly R/N) with arch involvement.
      • Schaefer B.
      • Lewin M.
      • Stout K.
      • Gill E.
      • Prueitt A.
      • Byers P.
      • et al.
      The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.
      From an echocardiographic analysis, Schaefer and colleagues
      • Schaefer B.
      • Lewin M.
      • Stout K.
      • Gill E.
      • Prueitt A.
      • Byers P.
      • et al.
      The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.
      defined 3 shapes of the proximal aorta based on the relative dimensions of sinuses of Valsalva, STJ, and tubular segment: type N, with dilation of the sinuses with preservation of the STJ; type A, dilation of the tubular aorta with preserved STJ; and type E, dilation of the STJ with preserved sinus of Valsalva, regardless of the diameter of tubular aorta.
      Finally, Park and associates
      • Park C.B.
      • Greason K.L.
      • Suri R.M.
      • Michelena H.I.
      • Schaff H.V.
      • Sundt III, T.M.
      Fate of nonreplaced sinuses of Valsalva in bicuspid aortic valve disease.
      proposed a classification scheme of BAV aortic phenotypes in a surgical study based on the segment involved (root vs tubular aorta) in the aneurysmal disease. These authors classified “type I” dilatation as that involving the tubular ascending aorta only, “type II” involving both the tubular ascending aorta and the root, and “type III” confined to the aortic root.
      • Park C.B.
      • Greason K.L.
      • Suri R.M.
      • Michelena H.I.
      • Schaff H.V.
      • Sundt III, T.M.
      Fate of nonreplaced sinuses of Valsalva in bicuspid aortic valve disease.
      In a recent longitudinal study that sought to validate the 3 different echocardiography-based BAV phenotypic classifications of the proximal aorta,
      • Schaefer B.
      • Lewin M.
      • Stout K.
      • Gill E.
      • Prueitt A.
      • Byers P.
      • et al.
      The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape.
      • Della Corte A.
      • Bancone C.
      • Quarto C.
      • Dialetto G.
      • Covino F.E.
      • Scardone M.
      • et al.
      Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression.
      • Park C.B.
      • Greason K.L.
      • Suri R.M.
      • Michelena H.I.
      • Schaff H.V.
      • Sundt III, T.M.
      Fate of nonreplaced sinuses of Valsalva in bicuspid aortic valve disease.
      only the classification system distinguishing between ascending phenotype and root phenotype showed a potential prognostic value in predicting growth rate of the aorta over time.
      • Della Corte A.
      • Bancone C.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • Montibello M.V.
      • et al.
      The ascending aorta with bicuspid aortic valve: a phenotypic classification with potential prognostic significance.
      Consistent with these findings, a prior longitudinal study demonstrated that the root phenotype is associated with a significantly greater risk of aortic events after isolated AVR.
      • Girdauskas E.
      • Disha K.
      • Raisin H.H.
      • Secknus M.A.
      • Borger M.A.
      • Kuntze T.
      Risk of late aortic events after an isolated aortic valve replacement for bicuspid aortic valve stenosis with concomitant ascending aortic dilation.
      This classification system also has practical value, because the root phenotype frequently requires a Bentall or valve-sparing procedure, whereas replacement of the tubular aorta is usually sufficient to treat the ascending phenotype (Figure 5). Of note, 2 aortic dissection series revealed that patients with BAV received a Bentall operation significantly more often (85%-94%) than patients with TAV (20%-30%) because of the presence of a preexisting root aneurysm or the involvement of the sinuses by the dissecting process.
      • Rylski B.
      • Desai N.D.
      • Bavaria J.E.
      • Vallabhajosyula P.
      • Moser W.
      • Pochettino A.
      • et al.
      Aortic valve morphology determines the presentation and surgical approach to acute type A aortic dissection.
      • Etz C.D.
      • von Aspern K.
      • Hoyer A.
      • Girrbach F.F.
      • Leontyev S.
      • Bakhtiary F.
      • et al.
      Acute type A aortic dissection: characteristics and outcomes comparing patients with bicuspid versus tricuspid aortic valve.
      It should be stressed that although valve morphology is a congenital feature of a patient with BAV, the aortic phenotype can change during life. That is, a proportion of patients with root phenotype can progress to an ascending phenotype over time.
      • Della Corte A.
      • Bancone C.
      • Buonocore M.
      • Dialetto G.
      • Covino F.E.
      • Manduca S.
      • et al.
      Pattern of ascending aortic dimensions predicts the growth rate of the aorta in patients with bicuspid aortic valve.
      Further research in this area will undoubtedly lead to further insights into BAV-aortopathy patterns. Hopefully, a single classification system will emerge that encompasses BAV morphology, BAV lesion, and location and extent of associated aortopathy in a clinically meaningful manner.
      Figure thumbnail gr5
      Figure 5Subdivision of proximal aortic involvement in BAV aortopathy.
      Reproduced with permission from Verma and Siu.
      • Verma S.
      • Siu S.C.
      Aortic dilatation in patients with bicuspid aortic valve.

      Symmetry Versus Asymmetry of Aortic Dilatation

      Symmetry versus asymmetry of aortic dilatation also may provide an important clue regarding the predominant pathogenesis of BAV aortopathy inasmuch as asymmetrical aortic involvement might be an indicator of rheological factors involved, whereas symmetrical involvement might be more predictive of genetically triggered vessel wall weakness. By “asymmetric dilatation,” predominant enlargement of the greater, outer curvature (usually referred to by the misnomer “convexity” as opposite to the lesser, inner curvature or “concavity”) of the tubular aorta is meant. Preoperative imaging methods can be used to identify asymmetric aneurysms.
      • Lu M.T.
      • Thadani S.R.
      • Hope M.D.
      Quantitative assessment of asymmetric aortic dilation with valve-related aortic disease.
      • Bauer M.
      • Gliech V.
      • Siniawski H.
      • Hetzer R.
      Configuration of the ascending aorta in patients with bicuspid and tricuspid aortic valve disease undergoing aortic valve replacement with or without reduction aortoplasty.
      Several studies found a significant correlation between functional BAV lesion (ie, BAV-AS) and asymmetric dilatation of the tubular aorta.
      • Bauer M.
      • Gliech V.
      • Siniawski H.
      • Hetzer R.
      Configuration of the ascending aorta in patients with bicuspid and tricuspid aortic valve disease undergoing aortic valve replacement with or without reduction aortoplasty.
      • Cotrufo M.
      • Della Corte A.
      The association of bicuspid aortic valve disease with asymmetric dilatation of the tubular ascending aorta: identification of a definite syndrome.
      Asymmetric patterns of histologic lesions and ECM protein expression have been demonstrated between the concavity (where less severe changes are observed) and the convexity (more severe structural changes) in such patients.
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Scholle T.
      • Fey B.
      • Theis B.
      • et al.
      Correlation between systolic transvalvular flow and proximal aortic wall changes in bicuspid aortic valve stenosis.
      • Cotrufo M.
      • Della Corte A.
      • De Santo L.S.
      • Quarto C.
      • De Feo M.
      • Romano G.
      • et al.
      Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results.
      A recent study looked at the expression of transforming growth factor (TGF) β-1 and matrix metalloproteinases (MMPs) in BAV aortopathy and found that wall areas that had been mapped as regions of increased WSS by preoperative 4D-flow MRI exhibited greater expression of these markers of vascular remodeling.
      • Guzzardi D.G.
      • Barker A.J.
      • van Ooij P.
      • Malaisrie S.C.
      • Puthumana J.J.
      • Belke D.D.
      • et al.
      Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.
      No similar study has thus far been performed in patients with BAV-AI.

      4. Histopathologic and Biomechanical Findings of Bicuspid Aortic Valve Aortopathy

      Histopathologic Studies

      BAV aortopathy consists of premature cystic medial degeneration in approximately one half of surgically excised BAVs.
      • Niwa K.
      • Perloff J.
      • Bhuta S.
      • Laks H.
      • Drinkwater D.
      • Child J.
      • et al.
      Structural abnormalities of great arterial walls in congenital heart disease: light and electron microscopic analyses.
      Histopathologic changes in the media have been well documented and specifically delineated for the BAV-associated aneurysms.
      • Cotrufo M.
      • Della Corte A.
      • De Santo L.S.
      • Quarto C.
      • De Feo M.
      • Romano G.
      • et al.
      Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results.
      • Fedak P.W.
      • de Sa M.P.
      • Verma S.
      • Nili N.
      • Kazemian P.
      • Butany J.
      • et al.
      Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation.
      • Bauer M.
      • Pasic M.
      • Meyer R.
      • Goetze N.
      • Bauer U.
      • Siniawski H.
      • et al.
      Morphometric analysis of aortic media in patients with bicuspid and tricuspid aortic valve.
      • Russo C.F.
      • Cannata A.
      • Lanfranconi M.
      • Vitali E.
      • Garatti A.
      • Bonacina E.
      Is aortic wall degeneration related to bicuspid aortic valve anatomy in patients with valvular disease?.
      • Della Corte A.
      • De Santo L.S.
      • Montagnani S.
      • Quarto C.
      • Romano G.
      • Amarelli C.
      • et al.
      Spatial patterns of matrix protein expression in dilated ascending aorta with aortic regurgitation: congenital bicuspid valve versus Marfan's syndrome.
      It is also well established that the aortic ECM plays an important role in maintaining the aorta through both the binding/storing secreted proteins and maintaining the structural integrity of the vascular wall.
      • Bauer M.
      • Pasic M.
      • Meyer R.
      • Goetze N.
      • Bauer U.
      • Siniawski H.
      • et al.
      Morphometric analysis of aortic media in patients with bicuspid and tricuspid aortic valve.
      The presence of thin, fragmented elastin fibers, reduced fibrillin-1 content,
      • Fedak P.W.
      • de Sa M.P.
      • Verma S.
      • Nili N.
      • Kazemian P.
      • Butany J.
      • et al.
      Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation.
      and decreased types I and III collagen have suggested elevated proteolytic activity.
      • Cotrufo M.
      • Della Corte A.
      • De Santo L.S.
      • Quarto C.
      • De Feo M.
      • Romano G.
      • et al.
      Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: preliminary results.
      • Bauer M.
      • Pasic M.
      • Meyer R.
      • Goetze N.
      • Bauer U.
      • Siniawski H.
      • et al.
      Morphometric analysis of aortic media in patients with bicuspid and tricuspid aortic valve.
      The degradation of ECM is under the balanced control of MMPs and their specific tissue inhibitors (tissue inhibitors of metalloproteinases [TIMPs]), which are secreted by vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells.
      • Didangelos A.
      • Yin X.
      • Mandal K.
      • Baumert M.
      • Jahangiri M.
      • Mayr M.
      Proteomics characterization of extracellular space components in the human aorta.
      Various studies have shown a disturbance in the ECM of surgically resected BAVs with increased activity of MMPs, with MMP-1, MMP-2, MMP-9, MMP-12, and MMP-14 (MT1-MMP) being most often implicated.
      • Kutz W.E.
      • Wang L.W.
      • Bader H.L.
      • Majors A.K.
      • Iwata K.
      • Traboulsi E.I.
      • et al.
      ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts.
      • Ikonomidis J.S.
      • Jones J.A.
      • Barbour J.R.
      • Stroud R.E.
      • Clark L.L.
      • Kaplan B.S.
      • et al.
      Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with bicuspid or tricuspid aortic valves.
      • Tzemos N.
      • Lyseggen E.
      • Silversides C.
      • Jamorski M.
      • Tong J.H.
      • Harvey P.
      • et al.
      Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta.
      • Wilton E.
      • Bland M.
      • Thompson M.
      • Jahangiri M.
      Matrix metalloproteinase expression in the ascending aorta and aortic valve.
      • LeMaire S.A.
      • Wang X.
      • Wilks J.A.
      • Carter S.A.
      • Wen S.
      • Won T.
      • et al.
      Matrix metalloproteinases in ascending aortic aneurysms: bicuspid versus trileaflet aortic valves.
      The critical role of MMP-2 as a key molecular mediator was supported by a recent meta-analysis.
      • Rabkin S.W.
      Differential expression of MMP-2, MMP-9 and TIMP proteins in thoracic aortic aneurysm - comparison with and without bicuspid aortic valve: a meta-analysis.
      Wang and colleagues
      • Wang Y.
      • Wu B.
      • Dong L.
      • Wang C.
      • Wang X.
      • Shu X.
      Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis.
      further showed MMP-2 as a circulating biomarker of aortic dilatation in patients with BAV.
      Like MMPs, the expression of TIMPs is controlled during tissue remodeling and physiologic conditions to maintain a balance in the metabolism of the ECM. Studies have demonstrated increased TIMP-1, TIMP-2, and TIMP-4 levels associated with BAV aortopathy.
      • Wilton E.
      • Bland M.
      • Thompson M.
      • Jahangiri M.
      Matrix metalloproteinase expression in the ascending aorta and aortic valve.
      Altered MMP/TIMP stoichiometry leads to apoptosis and degeneration of the aortic wall (ie, loss of elastic tissue and SMCs) and the eventual progression of aneurysms. Of note, histologic grading has revealed more extensive degradation of the ascending aortic wall in patient with Sievers 1 R/L fusion.
      • Russo C.F.
      • Cannata A.
      • Lanfranconi M.
      • Vitali E.
      • Garatti A.
      • Bonacina E.
      Is aortic wall degeneration related to bicuspid aortic valve anatomy in patients with valvular disease?.
      This has further been supported with data showing elevated proteolytic indices (ie, MMP abundance corrected for TIMP abundance) for MMP-1, MMP-2, MMP-9, and MMP-12.
      • Ikonomidis J.S.
      • Ruddy J.M.
      • Benton Jr., S.M.
      • Arroyo J.
      • Brinsa T.A.
      • Stroud R.E.
      • et al.
      Aortic dilatation with bicuspid aortic valves: cusp fusion correlates to matrix metalloproteinases and inhibitors.
      Consistent with findings in patients with Marfan syndrome,
      • Holm T.M.
      • Habashi J.P.
      • Doyle J.J.
      • Bedja D.
      • Chen Y.
      • van Erp C.
      • et al.
      Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice.
      early data point to the involvement of TGF-β signaling contributing to the progression of BAV aortopathy, although this remains somewhat controversial.
      • Girdauskas E.
      • Schulz S.
      • Borger M.A.
      • Mierzwa M.
      • Kuntze T.
      Transforming growth factor-beta receptor type II mutation in a patient with bicuspid aortic valve disease and intraoperative aortic dissection.
      • Paloschi V.
      • Gadin J.R.
      • Khan S.
      • Bjorck H.M.
      • Du L.
      • Maleki S.
      • et al.
      Aneurysm development in patients with a bicuspid aortic valve is not associated with transforming growth factor-beta activation.
      • Forte A.
      • Della Corte A.
      • Grossi M.
      • Bancone C.
      • Provenzano R.
      • Finicelli M.
      • et al.
      Early cell changes and TGFbeta pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis.
      Phillippi and co-workers
      • Phillippi J.A.
      • Green B.R.
      • Eskay M.A.
      • Kotlarczyk M.P.
      • Hill M.R.
      • Robertson A.M.
      • et al.
      Mechanism of aortic medial matrix remodeling is distinct in patients with bicuspid aortic valve.
      further characterized the medial matrix remodeling of the BAV and found unique patterns compared with TAV.
      • Phillippi J.A.
      • Green B.R.
      • Eskay M.A.
      • Kotlarczyk M.P.
      • Hill M.R.
      • Robertson A.M.
      • et al.
      Mechanism of aortic medial matrix remodeling is distinct in patients with bicuspid aortic valve.
      Grewal and co-workers
      • Grewal N.
      • Franken R.
      • Mulder B.J.
      • Goumans M.J.
      • Lindeman J.H.
      • Jongbloed M.R.
      • et al.
      Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy?.
      compared the histopathology of BAV, TAV, and Marfan aortic tissue and found both similarities and differences among all 3 groups with respect to parameters of matrix remodeling and vascular smooth muscle markers. The complexity of the histopathologic findings is substantial, and it is not clear what molecular pathways are unique to the BAV. The complexity is further confounded by the findings of Heng and colleagues.
      • Heng E.
      • Stone J.R.
      • Kim J.B.
      • Lee H.
      • MacGillivray T.E.
      • Sundt T.M.
      Comparative histology of aortic dilatation associated with bileaflet versus trileaflet aortic valves.
      In this recent study, tissue pathology was compared between TAV and patients with BAV at matched aortic diameters. At odds with conventional wisdom, more severe histologic abnormalities were found in TAV compared with BAVs, especially when stratified by diameter.
      In addition to ECM degradation, SMC loss is a prominent feature of BAV aortopathy. SMC phenotype, oxidative stress patterns, and responsiveness to oxidative stress appear altered in the BAV wall.
      • Forte A.
      • Della Corte A.
      • Grossi M.
      • Bancone C.
      • Provenzano R.
      • Finicelli M.
      • et al.
      Early cell changes and TGFbeta pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis.
      • Grewal N.
      • Gittenberger-de Groot A.C.
      • Poelmann R.E.
      • Klautz R.J.
      • Lindeman J.H.
      • Goumans M.J.
      • et al.
      Ascending aorta dilation in association with bicuspid aortic valve: a maturation defect of the aortic wall.
      • Phillippi J.A.
      • Klyachko E.A.
      • Kenny IV, J.P.
      • Eskay M.A.
      • Gorman R.C.
      • Gleason T.G.
      Basal and oxidative stress-induced expression of metallothionein is decreased in ascending aortic aneurysms of bicuspid aortic valve patients.
      • Mohamed S.A.
      • Radtke A.
      • Saraei R.
      • Bullerdiek J.
      • Sorani H.
      • Nimzyk R.
      • et al.
      Locally different endothelial nitric oxide synthase protein levels in ascending aortic aneurysms of bicuspid and tricuspid aortic valve.
      • Arcucci A.
      • Ruocco M.R.
      • Albano F.
      • Granato G.
      • Romano V.
      • Corso G.
      • et al.
      Analysis of extracellular superoxide dismutase and Akt in ascending aortic aneurysm with tricuspid or bicuspid aortic valve.
      • Phillippi J.A.
      • Eskay M.A.
      • Kubala A.A.
      • Pitt B.R.
      • Gleason T.G.
      Altered oxidative stress responses and increased type I collagen expression in bicuspid aortic valve patients.
      • Blunder S.
      • Messner B.
      • Aschacher T.
      • Zeller I.
      • Turkcan A.
      • Wiedemann D.
      • et al.
      Characteristics of TAV- and BAV-associated thoracic aortic aneurysms–smooth muscle cell biology, expression profiling, and histological analyses.
      Metallothionein, a free radical scavenger, expression is dysregulated, and consequent SMC cell viability is reduced in response to oxidative stress in the BAV. Regional differences in apoptotic activity also appear to be present comparing the concave and convex portions of the bicuspid aorta.
      • Mohamed S.A.
      • Misfeld M.
      • Hanke T.
      • Charitos E.I.
      • Bullerdiek J.
      • Belge G.
      • et al.
      Inhibition of caspase-3 differentially affects vascular smooth muscle cell apoptosis in the concave versus convex aortic sites in ascending aneurysms with a bicuspid aortic valve.
      Given the mounting evidence of regional differences in both the biology and the biomechanics of BAV aortopathy, it is likely that they correlate with one another. Aims to leverage these collective insights toward better diagnostics and risk adjudication are approaching.

      Biomechanical Studies

      Biomechanical functional testing of aortic tissues may provide further insights into BAV aortopathy. Ascending aortic wall properties are biomechanically anisotropic. Despite total collagen and elastin content and histopathologic findings that are similar, microarchitectural and biomechanical differences are apparent when comparing aortic wall characteristics in BAV versus TAV. The tensile strength, particularly in the circumferential and longitudinal directions, is higher in surgically resected ascending aortas in BAV compared with TAV,
      • Pichamuthu J.E.
      • Phillippi J.A.
      • Cleary D.A.
      • Chew D.W.
      • Hempel J.
      • Vorp D.A.
      • et al.
      Differential tensile strength and collagen composition in ascending aortic aneurysms by aortic valve phenotype.
      • Forsell C.
      • Bjorck H.M.
      • Eriksson P.
      • Franco-Cereceda A.
      • Gasser T.C.
      Biomechanical properties of the thoracic aneurysmal wall: differences between bicuspid aortic valve and tricuspid aortic valve patients.
      whereas the delamination strength of the aortic wall of the BAV is lower than the TAV.
      • Pasta S.
      • Phillippi J.A.
      • Gleason T.G.
      • Vorp D.A.
      Effect of aneurysm on the mechanical dissection properties of the human ascending thoracic aorta.
      Aortic wall remodeling characteristics in patients with BAV also appear distinct with more highly aligned collagen fibers, more undulating and less-aligned elastin fibers, thinner elastic lamellae, and greater distances between elastic lamellae.
      • Bauer M.
      • Pasic M.
      • Meyer R.
      • Goetze N.
      • Bauer U.
      • Siniawski H.
      • et al.
      Morphometric analysis of aortic media in patients with bicuspid and tricuspid aortic valve.
      • Phillippi J.A.
      • Green B.R.
      • Eskay M.A.
      • Kotlarczyk M.P.
      • Hill M.R.
      • Robertson A.M.
      • et al.
      Mechanism of aortic medial matrix remodeling is distinct in patients with bicuspid aortic valve.
      • Forsell C.
      • Bjorck H.M.
      • Eriksson P.
      • Franco-Cereceda A.
      • Gasser T.C.
      Biomechanical properties of the thoracic aneurysmal wall: differences between bicuspid aortic valve and tricuspid aortic valve patients.
      • Wagsater D.
      • Paloschi V.
      • Hanemaaijer R.
      • Hultenby K.
      • Bank R.A.
      • Franco-Cereceda A.
      • et al.
      Impaired collagen biosynthesis and cross-linking in aorta of patients with bicuspid aortic valve.
      • Tsamis A.
      • Phillippi J.A.
      • Koch R.G.
      • Pasta S.
      • D'Amore A.
      • Watkins S.C.
      • et al.
      Fiber micro-architecture in the longitudinal-radial and circumferential-radial planes of ascending thoracic aortic aneurysm media.
      Aortic stiffness is associated with progressive aortic dilatation and aneurysm formation, which is characteristic of BAV aortopathy.
      • Prakash A.
      • Adlakha H.
      • Rabideau N.
      • Hass C.J.
      • Morris S.A.
      • Geva T.
      • et al.
      Segmental aortic stiffness in children and young adults with connective tissue disorders: relationships with age, aortic size, rate of dilation, and surgical root replacement.
      A recent study of abdominal aortic aneurysms found that segmental stiffening of the aorta preceded aneurysm growth and introduced the concept that stiffening may act as an early mechanism triggering elastin breakdown and aneurysm growth.
      • Raaz U.
      • Zollner A.M.
      • Schellinger I.N.
      • Toh R.
      • Nakagami F.
      • Brandt M.
      • et al.
      Segmental aortic stiffening contributes to experimental abdominal aortic aneurysm development.
      Nonetheless, the evidence regarding cellular and molecular mechanisms for BAV aortopathy remains complex and contradictory, with a need for larger cohort, well-controlled studies.
      Although stimuli for BAV aortopathy are likely multifactorial, results from recent studies provide strong evidence that a hemodynamic (ie, rheologic) stimulus, the WSS, may change local matrix homeostasis and, in turn, ascending aortic structure and associated functional properties.
      • Guzzardi D.G.
      • Barker A.J.
      • van Ooij P.
      • Malaisrie S.C.
      • Puthumana J.J.
      • Belke D.D.
      • et al.
      Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.
      • Harloff A.
      • Wallis W.
      • Strecker C.
      • Brendecke S.
      • Simon J.
      • Weiller C.
      • et al.
      Global pulse wave velocity in 87 patients with acute ischemic stroke and aortic atherosclerosis.
      • Bock J.
      • Frydrychowicz A.
      • Lorenz R.
      • Hirtler D.
      • Barker A.J.
      • Johnson K.M.
      • et al.
      In vivo noninvasive 4D pressure difference mapping in the human aorta: phantom comparison and application in healthy volunteers and patients.
      • Stalder A.F.
      • Russe M.F.
      • Frydrychowicz A.
      • Bock J.
      • Hennig J.
      • Markl M.
      Quantitative 2D and 3D phase contrast MRI: optimized analysis of blood flow and vessel wall parameters.
      • Harloff A.
      • Nussbaumer A.
      • Bauer S.
      • Stalder A.F.
      • Frydrychowicz A.
      • Weiller C.
      • et al.
      In vivo assessment of wall shear stress in the atherosclerotic aorta using flow-sensitive 4D MRI.
      • van Ooij P.
      • Potters W.V.
      • Nederveen A.J.
      • Allen B.D.
      • Collins J.
      • Carr J.
      • et al.
      A methodology to detect abnormal relative wall shear stress on the full surface of the thoracic aorta using four-dimensional flow MRI.
      WSS is known to affect MMP2 levels
      • den Reijer P.M.
      • Sallee III, D.
      • van der Velden P.
      • Zaaijer E.R.
      • Parks W.J.
      • Ramamurthy S.
      • et al.
      Hemodynamic predictors of aortic dilatation in bicuspid aortic valve by velocity-encoded cardiovascular magnetic resonance.
      and has been implicated in the development of aortopathy.
      • Hope M.D.
      • Hope T.A.
      • Meadows A.K.
      • Ordovas K.G.
      • Urbania T.H.
      • Alley M.T.
      • et al.
      Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns.
      • Hope M.D.
      • Hope T.A.
      • Crook S.E.
      • Ordovas K.G.
      • Urbania T.H.
      • Alley M.T.
      • et al.
      4D flow CMR in assessment of valve-related ascending aortic disease.
      Aortic WSS calculations demonstrate differences in regional and radial wall stresses,
      • Nathan D.P.
      • Xu C.
      • Plappert T.
      • Desjardins B.
      • Gorman III, J.H.
      • Bavaria J.E.
      • et al.
      Increased ascending aortic wall stress in patients with bicuspid aortic valves.
      • Pasta S.
      • Rinaudo A.
      • Luca A.
      • Pilato M.
      • Scardulla C.
      • Gleason T.G.
      • et al.
      Difference in hemodynamic and wall stress of ascending thoracic aortic aneurysms with bicuspid and tricuspid aortic valve.
      but how these differences correspond to aortic wall remodeling, biology, and clinical outcome is not yet known. Proof-of-concept data were recently obtained using a novel ex vivo tissue model. Atkins and co-workers
      • Atkins S.K.
      • Cao K.
      • Rajamannan N.M.
      • Sucosky P.
      Bicuspid aortic valve hemodynamics induces abnormal medial remodeling in the convexity of porcine ascending aortas.
      modeled regional WSS from a TAV compared with a BAV in an ex vivo porcine tissue model, and the impact of BAV-mediated WSS was determined on aortic wall remodeling. The investigators found cellular, molecular (ie, increased MMP-2 activity), and structural changes that are characteristic of human BAV aortopathy. As highlighted by the investigators, the study indicates that altered WSS resulting from a BAV can focally mediate aortic medial degradation. These unique experimental findings provide compelling support for an important role of hemodynamics in mediating BAV aortopathy.
      Recent advances in MRI have permitted unobstructed in vivo assessment of time-resolved 3-dimensional (3D) blood velocity, using a volumetric technique referred to as “4D flow MRI.” 4D flow MRI provides the unique ability to quantify complex 3D blood flow patterns in vivo and has facilitated new insights and discovery with respect to complex cardiovascular hemodynamics.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      • Barker A.J.
      • Markl M.
      • Burk J.
      • Lorenz R.
      • Bock J.
      • Bauer S.
      • et al.
      Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.
      • Markl M.
      • Geiger J.
      • Arnold R.
      • Stroh A.
      • Damjanovic D.
      • Foll D.
      • et al.
      Comprehensive 4-dimensional magnetic resonance flow analysis after successful heart transplantation resolves controversial intraoperative findings and reveals complex hemodynamic alterations.
      • Markl M.
      • Wegent F.
      • Zech T.
      • Bauer S.
      • Strecker C.
      • Schumacher M.
      • et al.
      In vivo wall shear stress distribution in the carotid artery: effect of bifurcation geometry, internal carotid artery stenosis, and recanalization therapy.
      • Harloff A.
      • Simon J.
      • Brendecke S.
      • Assefa D.
      • Helbing T.
      • Frydrychowicz A.
      • et al.
      Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke.
      • Harloff A.
      • Strecker C.
      • Dudler P.
      • Nussbaumer A.
      • Frydrychowicz A.
      • Olschewski M.
      • et al.
      Retrograde embolism from the descending aorta: visualization by multidirectional 3D velocity mapping in cryptogenic stroke.
      Multidimensional 4D flow MRI data (3 spatial dimensions describing 3D velocity over time) enables aortic blood flow visualization, quantification of regional flow and velocity,
      • Markl M.
      • Geiger J.
      • Arnold R.
      • Stroh A.
      • Damjanovic D.
      • Foll D.
      • et al.
      Comprehensive 4-dimensional magnetic resonance flow analysis after successful heart transplantation resolves controversial intraoperative findings and reveals complex hemodynamic alterations.
      • Bock J.
      • Frydrychowicz A.
      • Stalder A.F.
      • Bley T.A.
      • Burkhardt H.
      • Hennig J.
      • et al.
      4D phase contrast MRI at 3 T: effect of standard and blood-pool contrast agents on SNR, PC-MRA, and blood flow visualization.
      • Frydrychowicz A.
      • Arnold R.
      • Harloff A.
      • Schlensak C.
      • Hennig J.
      • Langer M.
      • et al.
      Images in cardiovascular medicine. In vivo 3-dimensional flow connectivity mapping after extracardiac total cavopulmonary connection.
      • Markl M.
      • Harloff A.
      • Bley T.A.
      • Zaitsev M.
      • Jung B.
      • Weigang E.
      • et al.
      Time-resolved 3D MR velocity mapping at 3T: improved navigator-gated assessment of vascular anatomy and blood flow.
      and WSS quantification.
      • Bock J.
      • Frydrychowicz A.
      • Lorenz R.
      • Hirtler D.
      • Barker A.J.
      • Johnson K.M.
      • et al.
      In vivo noninvasive 4D pressure difference mapping in the human aorta: phantom comparison and application in healthy volunteers and patients.
      • Stalder A.F.
      • Russe M.F.
      • Frydrychowicz A.
      • Bock J.
      • Hennig J.
      • Markl M.
      Quantitative 2D and 3D phase contrast MRI: optimized analysis of blood flow and vessel wall parameters.
      • Harloff A.
      • Nussbaumer A.
      • Bauer S.
      • Stalder A.F.
      • Frydrychowicz A.
      • Weiller C.
      • et al.
      In vivo assessment of wall shear stress in the atherosclerotic aorta using flow-sensitive 4D MRI.
      • van Ooij P.
      • Potters W.V.
      • Nederveen A.J.
      • Allen B.D.
      • Collins J.
      • Carr J.
      • et al.
      A methodology to detect abnormal relative wall shear stress on the full surface of the thoracic aorta using four-dimensional flow MRI.
      • Garcia J.
      • Markl M.
      • Schnell S.
      • Allen B.
      • Entezari P.
      • Mahadevia R.
      • et al.
      Evaluation of aortic stenosis severity using 4D flow jet shear layer detection for the measurement of valve effective orifice area.
      • Barker A.J.
      • Lanning C.
      • Shandas R.
      Quantification of hemodynamic wall shear stress in patients with bicuspid aortic valve using phase-contrast MRI.
      Recent MRI studies provide strong evidence that valve-mediated local flow dynamics
      • Barker A.J.
      • Markl M.
      • Burk J.
      • Lorenz R.
      • Bock J.
      • Bauer S.
      • et al.
      Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.
      and regional differences in WSS
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      are associated with changes in regional aortic wall histology and proteolytic events,
      • Guzzardi D.G.
      • Barker A.J.
      • van Ooij P.
      • Malaisrie S.C.
      • Puthumana J.J.
      • Belke D.D.
      • et al.
      Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping.
      which are known to drive adverse aortic remodeling. Early studies used less-sophisticated MRI techniques (2-dimensional [2D] phase-contrast MRI) to demonstrate BAV-mediated changes in flow and WSS
      • Barker A.J.
      • Lanning C.
      • Shandas R.
      Quantification of hemodynamic wall shear stress in patients with bicuspid aortic valve using phase-contrast MRI.
      and their association with aortic enlargement.
      • Della Corte A.
      • Bancone C.
      • Conti C.A.
      • Votta E.
      • Redaelli A.
      • Del Viscovo L.
      • et al.
      Restricted cusp motion in right-left type of bicuspid aortic valves: a new risk marker for aortopathy.
      Subsequent 4D flow MRI studies have conclusively documented that aortic WSS is increased in subjects with BAV independent of stenosis severity when compared with age- and aortic size–matched controls.
      • Barker A.J.
      • Markl M.
      • Burk J.
      • Lorenz R.
      • Bock J.
      • Bauer S.
      • et al.
      Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.
      Moreover, regional variation of WSS within the aorta is dependent on aortic valve fusion phenotype
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      • Barker A.J.
      • Markl M.
      • Burk J.
      • Lorenz R.
      • Bock J.
      • Bauer S.
      • et al.
      Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic 3D outflow patterns, wall shear stress and expression of aortopathy.
      and is associated with aortic diameter.
      • Bissell M.M.
      • Hess A.T.
      • Biasiolli L.
      • Glaze S.J.
      • Loudon M.
      • Pitcher A.
      • et al.
      Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type.
      A recent study with 30 patients with BAV and 30 age-appropriate TAV controls provided evidence that altered aortic hemodynamics may be a pathophysiologic mechanism by which R/L or R/N BAV fusion patterns influence the expression of aortopathy.
      • Mahadevia R.
      • Barker A.J.
      • Schnell S.
      • Entezari P.
      • Kansal P.
      • Fedak P.W.
      • et al.
      Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy.
      Similar to the findings of Atkins and Sucosky in the porcine model, aortic hemodynamic alterations were found to be related to medial wall degeneration.
      • Atkins S.K.
      • Cao K.
      • Rajamannan N.M.
      • Sucosky P.
      Bicuspid aortic valve hemodynamics induces abnormal medial remodeling in the convexity of porcine ascending aortas.
      In a recent study that included both in vivo 4D flow MRI and aortic tissue resection in 20 patients with BAV, elastin content and structure were severely disrupted in regions of high WSS with a shift in the expression of specific MMPs and TGF-β. Girdauskas and colleagues
      • Girdauskas E.
      • Rouman M.
      • Disha K.
      • Scholle T.
      • Fey B.
      • Theis B.
      • et al.
      Correlation between systolic transvalvular flow and proximal aortic wall changes in bicuspid aortic valve stenosis.
      found a similar correlation between systolic transvalvular flow patterns and proximal aortic wall changes in the setting of BAV-AS. With more extensive investigation, it is conceivable that quantitative metrics of valve-mediated hemodynamics could be used to guide more precise and individualized surgical resection strategies beyond contemporary empirical size thresholds.

      5. Diagnostic Modalities

      General Vascular Imaging Concepts

      Transthoracic echocardiography (TTE) is the recommended imaging modality for the initial assessment of the aortic valve and thoracic aorta, including the assessment of hemodynamic valve function (Table 3; Figures 6 and 7).
      • Michelena H.I.
      • Della Corte A.
      • Prakash S.K.
      • Milewicz D.M.
      • Evangelista A.
      • Enriquez-Sarano M.
      Bicuspid aortic valve aortopathy in adults: incidence, etiology, and clinical significance.
      If any part of the examination is not possible by TTE, CT or MRI is recommended to assess the presence and extent of aortopathy (Figures 8 and 9). Hemodynamic valve assessment also can be performed by MRI,
      • Malaisrie S.C.
      • Carr J.
      • Mikati I.
      • Rigolin V.
      • Yip B.K.
      • Lapin B.
      • et al.
      Cardiac magnetic resonance imaging is more diagnostic than 2-dimensional echocardiography in determining the presence of bicuspid aortic valve.
      although TTE remains the gold standard. TTE assessment of aortic valve function is usually sufficient, but transesophageal echocardiography (TEE) should be performed in patients with AI that is difficult to quantify with TTE. BAV-AI may result in an eccentric jet that can be better visualized with TEE, particularly if patients have less-than-severe AI by TTE and unexplained left ventricular dilation or dysfunction. In addition, TEE may best determine the mechanism of AI when aortic valve repair is being considered.
      Table 3Recommendations for initial imaging of the aorta in patients with bicuspid aortic valve
      RecommendationClass/LOE
      TTE is the initial imaging modality of choice for assessment of the aortic valve and thoracic aorta in patients with BAV.I/C
      • Hiratzka L.F.
      • Bakris G.L.
      • Beckman J.A.
      • Bersin R.M.
      • Carr V.F.
      • Casey Jr., D.E.
      • et al.
      2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
      • Goldstein S.A.
      • Evangelista A.
      • Abbara S.
      • Arai A.
      • Asch F.M.
      • Badano L.P.
      • et al.
      Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance.
      The entire thoracic aorta should be measured by TTE, reporting each aortic segment separately in millimeters: root (sinuses of Valsalva), STJ, tubular ascending aorta (proximal, mid, and distal), arch, and descending thoracic aorta (Figure 11). Maximum diameter, regardless of location, should be reported. Aortic coarctation should be ruled out with Doppler evaluation of the descending thoracic aorta and abdominal aorta.I/C
      • Hiratzka L.F.
      • Bakris G.L.
      • Beckman J.A.
      • Bersin R.M.
      • Carr V.F.
      • Casey Jr., D.E.
      • et al.
      2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
      • Goldstein S.A.
      • Evangelista A.
      • Abbara S.
      • Arai A.
      • Asch F.M.
      • Badano L.P.
      • et al.
      Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance.
      • Warnes C.A.
      • Williams R.G.
      • Bashore T.M.
      • Child J.S.
      • Connolly H.M.
      • Dearani J.A.
      • et al.
      ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease).
      If TTE cannot visualize any aortic segment, any segment measures ≥45 mm, or aortic coarctation cannot be ruled out, recommend assessment of the entire thoracic aorta with ECG-gated cardiac MRA or CTA.I/C
      • Michelena H.I.
      • Khanna A.D.
      • Mahoney D.
      • Margaryan E.
      • Topilsky Y.
      • Suri R.M.
      • et al.
      Incidence of aortic complications in patients with bicuspid aortic valves.
      • Borger M.A.
      • Preston M.
      • Ivanov J.
      • Fedak P.W.
      • Davierwala P.
      • Armstrong S.
      • et al.
      Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease?.
      If a patient is undergoing cardiac surgery and root or tubular ascending aorta measure 40-44 mm by TTE, recommend assessment of the thoracic aorta with MRA or CTA before surgery.I/C
      • Michelena H.I.
      • Khanna A.D.
      • Mahoney D.
      • Margaryan E.
      • Topilsky Y.
      • Suri R.M.
      • et al.
      Incidence of aortic complications in patients with bicuspid aortic valves.
      • Borger M.A.
      • Preston M.
      • Ivanov J.
      • Fedak P.W.
      • Davierwala P.
      • Armstrong S.
      • et al.
      Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease?.
      • Eleid M.F.
      • Forde I.
      • Edwards W.D.
      • Maleszewski J.J.
      • Suri R.M.
      • Schaff H.V.
      • et al.
      Type A aortic dissection in patients with bicuspid aortic valves: clinical and pathological comparison with tricuspid aortic valves.