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1、Bicuspid Aortic Valve Disease New Insights in Pathogenesis & Treatment,Lee E. Errett MD, FRCSC, FRCS Chief, Division of Cardiovascular and Thoracic Surgery, St. Michaels Hospital Terrence Donnelly Cardiac Centre. Professor, University of Toronto,Overview,What causes BAV and its complications? BAV as
2、sociated aortopathy: Mechanisms Patterns of BAV associated aortopathy When should the aorta be replaced?,Bicuspid Aortic Valve Disease,Background,1. Most common congenital cardiac defect One in 3 will develop complications Incidence 1-2% (25 million in China) Most common cause of AS/AI in patients u
3、nder 70 Causes more morbidity than all other congenital disorders combined Not affected by race or geography Male: Female ratio of 3:1 Inheritance unclear (autosomal dominant?),Bicuspid Aortic Valve (BAV),Fedak P, Verma S, Circulation 2002; 106(8):900-4,Etiology and Development of Congenital BAV,Abn
4、ormal aortic cusp formation. Adjacent cusps fail to separate, resulting in a single aberrant cusp. Phenotypic continuum (unicuspid, bicuspid, tricuspid),Fedak P, Verma S, Circulation 2002; 106(8):900-4 Fedak, David, Borger, Verma, Expert Rev Cardiovasc Ther 2005,Bicuspid Aortic Valve (BAV) Morpholog
5、y,Sabet et al, Mayo Clin Proc, 1994;74:14-26,Leaflet Position,Anterior-Posterior,Left-Right,Etiology and Mechanisms,Abnormal blood flow through aortic valve during valvulogenesis results in a failure of cusp seperation Embryonic theory (abnormalities in conotruncal seperation) Cono-truncus divided b
6、y the spiral conotruncal septum Right & left aortic leaflets form at the junction of ventricular & arterial ends of conotruncal channel,Coronary Anomalies in BAV,Present in large proportion of patients,Left dominant system with short left main,180 separation,Left coronary from PA (rare) Stenosis of
7、left coronary ostium (rare),Presentation of BAV Disease: Correlation With Patient Age,Pediatric patients: AS or endocarditis,Young adult: AI, endocarditis or dissection,Middle age adults: AS or dissection,Elderly adults: AS,Anomalies Associated With BAV Disease,Aortic dilation and aneurysm formation
8、,Aortic dissection,Aortic coarctation and interruption,Coronary anomalies (dominant Cx),VSD, bicuspid PV (rare) Williams syndrome and Turners,BAV and Aortic Dissection,BAV is associated with a 9 fold increase in risk,BAV found in upward of 15% of type A,70% of cases have normal valvular function,Mos
9、t common cause of aortic dissection,Molecular 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 -
10、Etiology and mechanisms unknown,Aortic Dilatation and BAV,Aortic Dilatation and BAV,Poor Correlation Between Degree of AS and Aortic Dilation,Magrad et al. JTCVS 2001,Media,Intima,Adventitia,Human Aorta,Elastic Lamellae of Media,The Role of Fibrillin-1,Functional Role - Maintains Tissue Elasticity -
11、 Fbn-1 gene defect (Marfan Syndrome) - Altered fibrillin-1 content - Aortic dilation and dissection,Developmental Role - Directs formation of valve and aorta,PNAS 1999; 96: 3891,Fibrillin-1 Deficient Mouse: Progressive Aortic Dilation,Verma S, Circ Res 2001; 88(1): 37,Fibrillin-1 Deficient Mouse: Ma
12、trix Disruption in Aortic Media,Normal Mouse,Fbn-1 Deficient Mouse,Disrupted Matrix Aortic Aneurysm,Normal Matrix No Aortic Dilation,Fibrillin-1 Deficient Mouse: Fibrillin-1 Deficient Tissues Release MMPs,Fibrillin-1 Deficiency,Matrix Disruption in BAV Patients,Objective,Hypothesis In BAV patients,
13、fibrillin-1 deficiency and increased MMP matrix degradation result in aortic dilation,Methods,Aorta,Fibrillin-1 Content Immunohistochemistry Fluorescence Microscopy Quantitative Image Analysis,Elastin & Collagen CNBr Digestion Hydroxyproline Content,MMP Activity MMP Gelatin Zymography Quantitative I
14、mage Analysis,Fibrillin-1 Deficiency,SD,Fedak, Verma, et al. JTCVS 2003; 126(3): 797-806,Increased MMP-2 Activity,Active,BAV Aorta,TAV Aorta,Latent,Increased MMP-2 Activity,Novel Mechanism of Aortic Dilation,FBN-1 Gene Mutation (?),Decreased FBN-1 Production,FBN-1 Deficiency,SMC Detachment from Elas
15、tin Laminae,MMP-2 Release,Matrix Degradation,Apoptosis,Medial Degeneration,Aortic Dilatation,A Novel Mechanism for Aortic Dilatation,Anatomic Patterns of Aortic Dilation Custom Tailoring Required,Patterns of Aortic Dilation in Bicuspid Aortic Valves,A: aortoventricular jxn B: Sinuses of Valsalva C:
16、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 diaphragm,Patterns of Aortic Dilation in Bicuspid Aortic Valves,Root (Sinuses) Dilation (Valved Conduit or Repair),Asce
17、nding Aorta (Supracoronary Graft),Ascending+Transverse Arch (RAA and Hemiarch),Aortopathy in Bicuspid Valve,When Should the Ascending Aorta Be Replaced in Patients with Bicuspid Aortic Valve Disease?,Borger, Fedak, Verma et al. JTCVS 2005,Current recommendations for replacement of the ascending aort
18、a (RAA): 5.5 cm in diameter 5.0 cm in Marfans patients,Kouchoukos 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
19、Lower threshold for RAA in BAV patients (because of congenital aortopathy)?,When Should RAA be Done in BAV Patients?,To determine incidence of long-term ascending aorta complications (aneurysm, dissection or sudden death) and survival in BAV pts with mild aortic dilatation (40 50 mm) versus no dilat
20、ation,To determine the threshold diameter for RAA in BAV patients undergoing aortic valve surgery,Purpose of Study,Diameter of ascending aorta determined by direct measurement, TEE, or intaoperative description: “normal” less than 4.0 cm “mildly dilated” 4.0 4.4 cm “moderately dilated” 4.5 4.9 cm,Pa
21、tients with aortic diameters 5.0 cm underwent RAA and were excluded,Methods,Retrospective review of 201 BAV pts undergoing aortic valve replacement,BAV Dysfunction,Prevalence (%),JTCVS 2005,Results,Valve Prosthesis,Prevalence (%),JTCVS 2005,Results,Causes of Reoperation,Total reoperations = 44 (22%)
22、,Results,Results,JTCVS 2005,Freedom from Aortic Complications,JTCVS 2005,Results,Long-Term Survival,BAV disease is associated with a moderate risk of ascending aortic complications after AVR,In BAV patients at the time of AVR, replace the ascending aorta if 4.5 cm in diameter to reduce aortic compli
23、cations and improve long-term survival,Implications,An approach to ascribe moderate dilation to “post-stenotic dilation” may be misleading,Surgical Options,Isolated AS/AI and AD 4.5 AVR + RAA (supracoronary) Reduction aortoplasty Bentall Valve Repair No valvular involvement and AD 4.5-5 Rate of grow
24、th,Toronto General Hospital,ROOT,VALVE,Composite Graft,Separate Graft,N=89,N=50,Mechanical (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 up,Summary,BAV is a common congenital car
25、diac 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
26、valve dysfunction, endocarditis, dilation/dissection. Several distinct patterns of aortic dilation are prevalent, and require custom tailoring At surgery, attention to early replacement of aorta (4.5) should be given At SMH we have a special interest in following patients with BAV, with or without v
27、alvular lesions, to evaluate natural history and timing of surgery,Targeting MMP in Aneurysm Remodeling and Rupture,Verma S, NEJM 2006,Ongoing Areas of Interest,Can statins alter the natural history of BAV disease? Verma S, Errett L et al. Am J Physiol 2005 Does eNOS deficiency and BAV share similar gene loci? Are patients with BAV predisposed to systemic endothelial dysfunction? Verma S, Anderson TJ. CCC 2006 BAV v TAV gene profiling (collaboration with Dr. Robert Roberts) Prospective evaluation of ascending aortic strategy in BAV with AS,