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Bicuspid Aortic Valve DiseaseNew Insights in Pathogenesis & TreatmentChief, Division of Cardiovascular and Thoracic Surgery, St. Michaels HospitalTerrence Donnelly Cardiac Centre.Professor, University of TorontoOverview 1. What causes BAV and its complications?2. BAV associated aortopathy: Mechanisms3. Patterns of BAV associated aortopathy4. When should the aorta be replaced?Bicuspid Aortic Valve DiseaseBackground 1. Most common congenital cardiac defect2. One in 3 will develop complications3. Incidence 1-2% (25 million in China)4. Most common cause of AS/AI in patients under 705. Causes more morbidity than all other congenital disorders combined6. Not affected by race or geography7. Male: Female ratio of 3:18. Inheritance unclear (autosomal dominant?)Bicuspid Aortic Valve (BAV)Fedak P, Verma S, Circulation 2002; 106(8):900-4Etiology and Development of Congenital BAV1. Abnormal aortic cusp formation.2. Adjacent cusps fail to separate, resulting in a single aberrant cusp. 3. Phenotypic continuum (unicuspid, bicuspid, tricuspid)Fedak P, Verma S, Circulation 2002; 106(8):900-4Fedak, David, Borger, Verma, Expert Rev Cardiovasc Ther 2005 Bicuspid Aortic Valve (BAV) MorphologySabet et al, Mayo Clin Proc, 1994;74:14-26Leaflet PositionAnterior-PosteriorLeft-RightEtiology and MechanismsnAbnormal blood flow through aortic valve during valvulogenesis results in a failure of cusp seperationnEmbryonic theory (abnormalities in conotruncal seperation)nCono-truncus divided by the spiral conotruncal septum nRight & left aortic leaflets form at the junction of ventricular & arterial ends of conotruncal channelCoronary Anomalies in BAVPresent in large proportion of patientsLeft dominant system with short left main180 separationLeft coronary from PA (rare)Stenosis of left coronary ostium (rare)Presentation of BAV Disease: Correlation With Patient AgePediatric patients: AS or endocarditisYoung adult: AI, endocarditis or dissectionMiddle age adults: AS or dissectionElderly adults: ASAnomalies Associated With BAV DiseaseAortic dilation and aneurysm formationAortic dissectionAortic coarctation and interruptionCoronary anomalies (dominant Cx)VSD, bicuspid PV (rare)Williams syndrome and Turners BAV and Aortic DissectionBAV is associated with a 9 fold increase in riskBAV found in upward of 15% of type A70% of cases have normal valvular functionMost common cause of aortic dissectionMolecular Mechanisms of Aortic Dilatation in Bicuspid Aortic Valve Disease: Role of Matrix Remodeling Fedak, Verma, et al. JTCVS 2003; 126(3): 797-806 - 50% of young asymptomatic patients - Independent of valve function - Associated degeneration of aortic media - Etiology and mechanisms unknown Aortic Dilatation and BAV Aortic Dilatation and BAV Poor Correlation Between Degree of AS and Aortic DilationMagrad et al. JTCVS 2001MediaIntimaAdventitiaHuman AortaElastic Lamellae of Media Elastin &CollagenSmooth Muscle Cells Fibrillin-1MicrofibrilsThe Role of Fibrillin-1 Functional Role- Maintains Tissue Elasticity- Fbn-1 gene defect (Marfan Syndrome)- Altered fibrillin-1 content- Aortic dilation and dissection Developmental Role- Directs formation of valve and aortaPNAS 1999; 96: 3891 Fibrillin-1 Deficient Mouse: Progressive Aortic Dilation Verma S, Circ Res 2001; 88(1): 37Fibrillin-1 Deficient Mouse:Matrix Disruption in Aortic MediaNormal MouseFbn-1 Deficient MouseDisrupted MatrixAortic AneurysmNormal MatrixNo Aortic DilationFibrillin-1 Deficient Mouse:Fibrillin-1 Deficient Tissues Release MMPs Fibrillin-1 DeficiencyIncreased Matrix Metalloproteinases (MMP) Matrix DisruptionAortic DilationMatrix Disruption in BAV PatientsAORTIC MEDIATricuspid AV (TAV)Bicuspid AV (BAV)Objective HypothesisIn BAV patients, fibrillin-1 deficiency and increased MMP matrix degradation result in aortic dilation Methods AortaFibrillin-1 ContentImmunohistochemistryFluorescence MicroscopyQuantitative Image Analysis Elastin & Collagen CNBr DigestionHydroxyproline Content MMP ActivityMMP Gelatin ZymographyQuantitative Image Analysis *102030Fibrillin-1Mean IOD Fibrillin-1 DeficiencySDFedak, Verma, et al. JTCVS 2003; 126(3): 797-806 Increased MMP-2 ActivityActiveBAV AortaTAV AortaLatent*0100020003000MMP-2Mean Activity TAVBAVIncreased MMP-2 ActivityNovel Mechanism of Aortic DilationFBN-1 Gene Mutation (?)Decreased FBN-1 ProductionFBN-1 DeficiencySMC Detachment from Elastin LaminaeMMP-2 ReleaseMatrix DegradationApoptosisMedial DegenerationAortic DilatationA Novel Mechanism for Aortic DilatationSecondaryEventsAnatomic Patterns of Aortic DilationCustom Tailoring RequiredPatterns of Aortic Dilation in Bicuspid Aortic Valves A: aortoventricular jxn B: Sinuses of Valsalva C: Sinotubular jxn D: Tubular ascending aorta E: Proximal innominate F: Distal innominate G: Proximal left subclavian H: Distal left subclavian I: Proximal descending J: Descending at diaphragmPatterns of Aortic Dilation in Bicuspid Aortic ValvesRoot (Sinuses) Dilation (Valved Conduit or Repair)Ascending Aorta(Supracoronary Graft)Ascending+Transverse Arch(RAA and Hemiarch)Aortopathy in Bicuspid ValveBorger, Fedak, Verma et al. JTCVS 2005Kouchoukos NT, Dougenis D. N Engl J Med 1997;336:1876-88 Optimal diameter for RAA in pts undergoing aortic valve surgery is unknown Hinge Point (6cm) may be different in BAV 30 times higher risk of post-operative dissection post AVR if AA 5.0cm Lower threshold for RAA in BAV patients (because of congenital aortopathy)? To determine the threshold diameter for RAA in BAV patients undergoing aortic valve surgery Patients with aortic diameters 5.0 cm underwent RAA and were excluded Prevalence (%)JTCVS 2005Prevalence (%)JTCVS 2005Causes of ReoperationSVD 28Aortic aneurysm 7 (+11)Endocarditis 3Pannus formation 2Aortic dissection 1Mitral regurg 1LVOT obstruction 1Heart transplant 1Total reoperations = 44 (22%)11 of these pts also had ascending aortic aneurysms012345678910 11 12 13 14 150102030405060708090100Years PostoperativelyFree from Composite Outcome (%)114 64 22 98 58 17 69 44 8 13 10 3 At 15 yrs4.5 mm43 15% p0.001JTCVS 2005Freedom from Aortic Complications012345678910 11 12 13 14 150102030405060708090100Years PostoperativelySurvival (%)114 64 22 98 58 17 69 44 8 13 10 3 At 15 yrs4.5 mm41 14% p=0.004JTCVS 2005Long-Term Survival In BAV patients at the time of AVR, replace the ascending aorta if 4.5 cm in diameter to reduce aortic complications and improve long-term survival An approach to ascribe moderate dilation to “post-stenotic dilation” may be misleadingToronto General HospitalComposite GraftSeparate GraftN=89N=50Mechanical (55%)Stented-Tissue (16%) Stentless-Tissue (29%) Mechanical (36%)Stented-Tissue (60%) Stentless-Tissue (4%) Aortic diameter increased in 9% by 4-8 mm over the follow upBAV is a common congenital cardiac malformation that occurs during valve development, perhaps due to aberrant gene expression.Disrupted ECM, endothelial injury and changes in cell-death pathways have been implicated in BAV associated aortopathy.BAV implies disease of entire aortic root, and ascending aorta, and predisposes to valve dysfunction, endocarditis, dilation/dissection.Several distinct patterns of aortic dilation are prevalent, and require custom tailoringAt surgery, attention to early replacement of aorta (4.5) should be givenAt SMH we have a special interest in following patients with BAV, with or without valvular lesions, to evaluate natural history and timing of surgeryTargeting MMP in Aneurysm Remodeling and RuptureVerma S, NEJM 2006Ongoing Areas of InterestCan statins alter the natural history of BAV disease? Verma S, Errett L et al. Am J Physiol 2005Does eNOS deficiency and BAV share similar gene loci? Are patients with BAV predisposed to systemic endothelial dysfunction? Verma S, Anderson TJ. CCC 2006BAV v TAV gene profiling (collaboration with Dr. Robert Roberts)Prospective evaluation of ascending aortic strategy in BAV with AS
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