Amit J. ThosaniAmit J. Thosani

10 September 200810 September 2008

Aortic StenosisAortic Stenosis

EpidemiologyEpidemiology Common due to:Common due to:

Aging population—3-5% prevalence in Aging population—3-5% prevalence in population >75population >75Relatively common incidence of bicuspid Relatively common incidence of bicuspid AoV (1-2% of population)AoV (1-2% of population)

Long latent period, asymptomatic Long latent period, asymptomatic progression from AVA 3-4 cmprogression from AVA 3-4 cm22 to 1.5 cm to 1.5 cm22

Additional reduction in valve area from ½ to Additional reduction in valve area from ½ to ¼ normal size usually results in symptoms¼ normal size usually results in symptoms

PathophysiologyPathophysiology Outflow obstruction results in:Outflow obstruction results in:

Concentric hypertrophy in response to increased LV pressures to maintain normal Concentric hypertrophy in response to increased LV pressures to maintain normal wall stress; initially preserved LVEDV and COwall stress; initially preserved LVEDV and CO

With increasing afterload from increasing obstruction, further hypertrophy results With increasing afterload from increasing obstruction, further hypertrophy results in:in:--increased O2 demand--increased O2 demand--decreased coronary perfusion pressure--decreased coronary perfusion pressure--intramyocardial arterial compression--intramyocardial arterial compression--interstitial fibrosis and diastolic dysfunction--interstitial fibrosis and diastolic dysfunctionUltimately resulting in myocardial ischemia and reduced contractilityUltimately resulting in myocardial ischemia and reduced contractility

Angina secondary to aboveAngina secondary to above

Dyspnea due to diastolic dysfunction and inadequate cardiac output in setting of Dyspnea due to diastolic dysfunction and inadequate cardiac output in setting of fixed obstructionfixed obstruction

Dizziness/syncope due to exercise induced vasodilation in setting of fixed output, Dizziness/syncope due to exercise induced vasodilation in setting of fixed output, baroreceptor abnormalities, arrhythmia (AF)baroreceptor abnormalities, arrhythmia (AF)

Heart failure: advanced disease, low output stateHeart failure: advanced disease, low output state

Progression of ASProgression of AS

Mean pressure gradient increase up Mean pressure gradient increase up to 10 mm Hg/year (mean 7 mm Hg)to 10 mm Hg/year (mean 7 mm Hg)

Aortic valve area decrease of 0.12 ± Aortic valve area decrease of 0.12 ± 0.19 cm0.19 cm22/year/year

Individual variability existsIndividual variability exists

Feigenbaum’s Echocardiography, Sixth Edition, 2005, pp 285-288.

Natural HistoryNatural History

Prognosis significantly worsens with onset of symptomsAverage survival with symptom onset: less than 2-3 yearsIncreased risk of sudden death

Etiologies Etiologies

Nonvalvular:Nonvalvular:

SubaorticSubaortic

SupravalvularSupravalvular

Valvular:Valvular:

Calcific (7Calcific (7thth or 8 or 8thth decade) decade)

Bicuspid (4Bicuspid (4thth or 5 or 5thth decade) decade)

Rheumatic: more common in developing Rheumatic: more common in developing nationsnations

Subaortic StenosisSubaortic Stenosis Fixed vs. Dynamic (HOCM)Fixed vs. Dynamic (HOCM)

Distinct morphologies of fixed obstruction:Distinct morphologies of fixed obstruction:--Thin membrane (most common): typically seen --Thin membrane (most common): typically seen proximal to aortic root/septum junctionproximal to aortic root/septum junction--Thick fibromuscular ridge--Thick fibromuscular ridge--LVOT hypoplasia--LVOT hypoplasia

Often associated with AROften associated with AR

Pathophysiology: LVOT abnormalities causing Pathophysiology: LVOT abnormalities causing LVOT obstruction/fibrosis, LV hypertrophy, LVOT obstruction/fibrosis, LV hypertrophy, hyperdynamic functionhyperdynamic function

Subaortic StenosisSubaortic Stenosis

Otto CM, Textbook of Clinical Echocardiography, 3rd Edition, 2004, pp. 283.

Similar CW doppler velocity profiles for valvular AS and subaortic membrane

Late systolic velocity peak with dynamic obstruction in HCM; change in velocity profile with provocative maneuvers

Supravalvular AS: Supravalvular AS: EtiologiesEtiologies

4 distinct inheritance patterns:4 distinct inheritance patterns:

Williams Syndrome: “elfin facies,” mental retardation, Williams Syndrome: “elfin facies,” mental retardation, hypercalcemia, failure to thrive, renovascular hypertension, hypercalcemia, failure to thrive, renovascular hypertension, short statureshort statureLikely autosomal dominant inheritance; may be related to Likely autosomal dominant inheritance; may be related to elastin gene mutation (chromosome 7q11.23)elastin gene mutation (chromosome 7q11.23)

Autosomal dominant familial form (without features of Autosomal dominant familial form (without features of Williams Syndrome)Williams Syndrome)

Sporadic form without family history Sporadic form without family history

Homozygous familial hypercholesterolemia (FH): Homozygous familial hypercholesterolemia (FH): Autosomal dominant disorder; up to 44% have supravalvar AS Autosomal dominant disorder; up to 44% have supravalvar AS Less frequent in heterozygotes, typically affecting adultsLess frequent in heterozygotes, typically affecting adults

Supravalvular AS: Supravalvular AS: MorphologiesMorphologies

HourglassHourglass

http://img.tfd.com/mosbycam/thumbs/500227-fx36.jpg

•Aortic medial thickening/disorganization cause constricting annular ridge superior to sinuses of Valsalva•Most common subtype

Membranous: fibrous/fibromuscular diaphragm with small opening stretched across aorta

Diffuse Hypoplasia

Supravalvular ASSupravalvular AS

Supravalvular ASSupravalvular AS

Youn, HJ, Chung, WS, Hong, SJ. Heart 2002; 88:438.

TEE Aortgraphy

Surgical repair is definitive therapyUsually performed at lower gradient levels than in valvular AS to prevent long term sequellaeOutcomes better for focal disease than diffuse hypoplasia

Valvular AS: EtiologiesValvular AS: EtiologiesA. Normal Aortic

Valve

B. Congenital Bicuspid Aortic Valve

C. Rheumatic Aortic Valve

D. Calcific Aortic Valve

Braunwauld’s Heart Disease

Congenital Valvular AS: Congenital Valvular AS: Unicuspid and BicuspidUnicuspid and Bicuspid

Unicuspid Aortic Valve:

•May cause severe obstruction in infancy

•Male:female 4:1

•Associated with coarctation, PDA

•Most common cause of fatal AS <1yr of age

Lewin MB, Otto CM. Circulation 111: 832, 2005.

www.med.yale.edu

Bicuspid Aortic Valve:•Typically normal function in childhood•Aortic stenosis presentation after 50 years of age•20% develop aortic regurgitation between ages 10-40, may require AVR•Increased risk of endocarditis•Associated with dilated ascending aorta

Rheumatic ASRheumatic AS Fusion of commissures Fusion of commissures

and cuspsand cusps

Leaflet vascularization, Leaflet vascularization, causing stiffening of causing stiffening of cusps free borderscusps free borders

Typically regurgitant and Typically regurgitant and stenoticstenotic

Rheumatic mitral disease Rheumatic mitral disease nearly always present in nearly always present in patients with rheumatic patients with rheumatic ASAS

http://phil.cdc.gov/PHIL_Images/02051999/00014/20G0014_lores.jpg

Calcific ASCalcific AS Disease process likely similar to vascular atherosclerosis: Disease process likely similar to vascular atherosclerosis:

inflammatory and proliferative changesinflammatory and proliferative changes

Risk Factors:Risk Factors:1. Age1. Age2. Elevated LDL and Lp(a)2. Elevated LDL and Lp(a)3. Diabetes3. Diabetes4. Hypertension4. Hypertension5. Cigarette smoking5. Cigarette smoking

Cytokine release by infiltrating T-lymphocytes and macrophages Cytokine release by infiltrating T-lymphocytes and macrophages promotes:promotes:1. Extracellular matrix remodelling1. Extracellular matrix remodelling2. Cellular proliferation2. Cellular proliferation3. Differentiation of subset of fibroblasts into myofibroblasts 3. Differentiation of subset of fibroblasts into myofibroblasts possessing smooth muscle cell propertiespossessing smooth muscle cell properties4. Lipid accumulation (LDL, oxidized by macrophages)4. Lipid accumulation (LDL, oxidized by macrophages)5. Subset of myofibroblasts differentiate into an osteoblast 5. Subset of myofibroblasts differentiate into an osteoblast phenotype, capable of calcium nodules and bone formationphenotype, capable of calcium nodules and bone formation

Freeman RV, Otto CM. Circulation 111: 3316, 2005.

AS: Fluid DynamicsAS: Fluid DynamicsLaminar flow in LVOT proximal to stenotic valve (arrowheads)

As blood nears stenotic orifice, flow accelerates in small zone proximal to valve

In stenotic orifice, narrowest high velocity laminar jet is formed downstream from the orifice (vena contracta)

Vena contracta is smaller than actual orifice (magnitude of difference described by discharge coefficient, which depends on orifice geometry and inertial/sheer stress fluid properties)

Non-laminar flow beyond the jet, with blood moving in multiple directions and velocities

Otto CM. Textbook of Clinical Echocardiography, 3rd edition, 2004. pp. 278.

AS: Fluid DynamicsAS: Fluid DynamicsPressure gradient across stenotic valve is related to Pressure gradient across stenotic valve is related to

velocity in the jet, first described by Bernoulli in 1738, velocity in the jet, first described by Bernoulli in 1738, later refined by Euler, first applied to stenotic aortic later refined by Euler, first applied to stenotic aortic valves by Hatle in 1979:valves by Hatle in 1979:

ΔΔP = ½ p (vP = ½ p (v2222- v- v11

22) + p () + p (dv/dtdv/dt))dxdx + + RR((vv))

ΔΔPP Pressure gradient across valve (mm Hg)Pressure gradient across valve (mm Hg)p p Mass density of blood (1.06 x 10Mass density of blood (1.06 x 1033 kg/m kg/m33))vv22 Velocity in stenotic jetVelocity in stenotic jetvv11 Velocity proximal to stenosisVelocity proximal to stenosis((dv/dtdv/dt))dxdx Time-varying velocity at each distance along Time-varying velocity at each distance along

flowstreamflowstreamRR((vv)) Constant for viscous resistanceConstant for viscous resistance

Modified BernoulliModified Bernoulli

ΔΔP = ½ p (vP = ½ p (v2222- v- v11

22) + p () + p (dv/dtdv/dt))dxdx + + RR((vv))

Eliminating terms for viscous losses and acceleration, using known Eliminating terms for viscous losses and acceleration, using known values for mass density of blood, and converting velocity to m/s values for mass density of blood, and converting velocity to m/s yields modified Bernoulli equation:yields modified Bernoulli equation:

ΔΔP = 4(vP = 4(v2222- v- v11

22))

If proximal velocity is < 1 m/s, modified Bernoulli is further If proximal velocity is < 1 m/s, modified Bernoulli is further simplified:simplified:

ΔΔP = 4vP = 4v22

Mean Pressure GradientMean Pressure Gradient

ΔΔPPmeanmean = = ΔΔPPmaxmax/1.45 + 2 mm Hg/1.45 + 2 mm Hg

Mean gradient is approximately 2/3 of Mean gradient is approximately 2/3 of the peak instantaneous gradientthe peak instantaneous gradient

Calculation of AVACalculation of AVA PlanimetryPlanimetry

Gorlin EquationGorlin Equation

AVA=(CO)/(HR)(SEP)(44.3)(√mean gradient)AVA=(CO)/(HR)(SEP)(44.3)(√mean gradient)

Hakki Equation (simplfication of Gorlin)Hakki Equation (simplfication of Gorlin)

AVA=(CO)/(√peak gradient)AVA=(CO)/(√peak gradient)

Continuity EquationContinuity Equation

AVA Calculation: AVA Calculation: Echocardiography vs. Echocardiography vs.

Invasive HemodynamicsInvasive HemodynamicsPeak aortic and left ventricular pressures do not occur simultaneously

Maximum instantaneous gradient is greater than peak-to-peak gradient

Echocardiography and cardiac catheterization may yield discrepant results

Continuity EquationContinuity Equation

SVLVOT=SVAo

CSALVOT x VTILVOT = CSAAo x VTIAo

AVA = (CSALVOT x VTILVOT )/VTIAo

LVOT diameter: Parasternal Long AxisVTILVOT: Pulsed doppler, apical VTIAo: CW doppler, highest recorded velocity

Simplified Continuity Equation:

Assuming VTILVOT/VTIAo = VLVOT/VAo, and assuming circular outflow tract area,

AVA = π(LVOT diameter)2/4 x VLVOT/VAo

Evaluation of AS SeverityEvaluation of AS Severity Maximal Aortic Valve Maximal Aortic Valve

Velocity:Velocity:

In asymptomatic AS In asymptomatic AS patients, AoV velocity is patients, AoV velocity is strongest predictor of strongest predictor of outcomes:outcomes:

≤≤3 m/s: death or AVR 3 m/s: death or AVR 8%/year8%/year

3-4 m/s: 17% per year3-4 m/s: 17% per year≥≥4 m/s: 40% per year4 m/s: 40% per year

Vmax Vmax (m/s)(m/s)

SeveritSeverityy

≥≥44 SevereSevere

3-43-4 ModeraModeratete

1.6-31.6-3 MildMild

≤ ≤ 1.51.5 NormalNormal

Otto CM, Burwash IG, Legget ME, et al. Circulation 1997; 95:2262-2270.

2006 AHA/ACC Guidelines

Evaluation of AS SeverityEvaluation of AS Severity

SeveritySeverity Mean Mean Gradient Gradient (mmHg)(mmHg)

AVA AVA (ACC/AHA(ACC/AHA) (cm) (cm22))

AVA AVA (BIDMC)(BIDMC)

(cm(cm22))

NormalNormal <5<5 3-43-4

MildMild <25<25 >1.5>1.5 >1.2>1.2

ModerateModerate 25-4025-40 1.0-1.51.0-1.5 0.8-1.20.8-1.2

SevereSevere >40>40 <1.0<1.0 <0.8<0.8

Imaging ChallengesImaging ChallengesParallel intercept angle between ultrasound beamand aortic jet ensures maximal measured Ao velocity, as cos θ =1.

Deviation from parallel underestimates jet velocity,which is squared in continuity equation, magnifyingthe error.

Intercept angle of less than 15 degrees result in error ≤ 5%.

Multiple velocity measurements taken in multiple views to ensure highest velocity measured.

Multiple other high velocity systolic jets that may be mistaken for AS:

Mitral regurgitationTricuspid regurgitationVSDPulmonic stenosis

Imaging ChallengesImaging Challenges

LV outflow diameter measurement LV outflow diameter measurement critical to accurate calculation of critical to accurate calculation of AVAAVA

Arrhythmia: variability in velocity Arrhythmia: variability in velocity depending on stroke volume and depending on stroke volume and preceding R-R intervalpreceding R-R interval

Challenges: Low Challenges: Low Gradient ASGradient AS

Definition: Severe AS (AVA<1.0 cmDefinition: Severe AS (AVA<1.0 cm22) with ) with transvalvular pressure gradient <30 mm Hgtransvalvular pressure gradient <30 mm Hg

Challenge is to differentiate low gradient AS Challenge is to differentiate low gradient AS patients who will benefit from AVR (“true patients who will benefit from AVR (“true stenosis”) from those who will notstenosis”) from those who will not

““Psedostenosis:” symptoms due primarily to LV Psedostenosis:” symptoms due primarily to LV dysfunction rather than valvular diseasedysfunction rather than valvular disease

Gorlin and Hakki equations underestimate AVA Gorlin and Hakki equations underestimate AVA when CO is lowwhen CO is low

Challenges: Low Challenges: Low Gradient ASGradient AS

AS Assessment with LV DysfunctionAS Assessment with LV Dysfunction

TherapyTherapy Surgical AVR is mainstay of treatmentSurgical AVR is mainstay of treatment

ACC/AHA Class IA Indications:ACC/AHA Class IA Indications:Symptomatic severe ASSymptomatic severe ASSevere AS in patients undergoing Severe AS in patients undergoing CABG, aortic, or other heart valve surgerySevere AS with LVEF less than 50%

Class IIA Indications:Moderate AS in patients undergoing CABG, aortic, or other heart valve surgery

Class IIBSevere AS in asymptomatic patients who have an abnormal response to exercise such as the development of symptoms or hypotension

Severe AS in asymptomatic patients with a high likelihood of rapid progression (as determined by age, valve calcification, and coronary heart disease).

Severe AS in asymptomatic patients in whom surgery might be delayed at the time of symptom onset

Mild AS in patients undergoing coronary artery bypass graft surgery in whom there is evidence, such as moderate to severe valve calcification, that progression may be rapid

Extremely severe AS (aortic valve area less than 0.6 cm2, mean gradient greater than 60 mmHg, and aortic jet velocity greater than 5.0 m/sec) in asymptomatic patients in whom the expected operative mortality is 1 percent or less

Medical TherapyMedical Therapy Association between AS progression and dyslipidemia Association between AS progression and dyslipidemia

Pohle K, Maffert R, Ropers D, et al. Pohle K, Maffert R, Ropers D, et al. CirculationCirculation 2001; 104(16); 1927- 2001; 104(16); 1927-32.32.

AS calcification and progression increased in patients with serum AS calcification and progression increased in patients with serum LDL>130 mg/dL LDL>130 mg/dL

SALTIRE Trial: Scottish Aortic Stenosis and Lipid Lowering Trial, SALTIRE Trial: Scottish Aortic Stenosis and Lipid Lowering Trial,

Impact on RegressionImpact on Regression (NEJM 2005; 352(23): 2389-97)(NEJM 2005; 352(23): 2389-97)

155 calcific AS patients (aortic jet velocity>2.5 m/s, calcification seen 155 calcific AS patients (aortic jet velocity>2.5 m/s, calcification seen on TTE, mean AVA 1.03 cmon TTE, mean AVA 1.03 cm22))Randomized to atorvastatin 80 mg vs. placeboRandomized to atorvastatin 80 mg vs. placeboNonclinical endpoints: change in aortic jet velocity and aortic valve Nonclinical endpoints: change in aortic jet velocity and aortic valve calcium scorecalcium score25 month follow up: no difference in progression of aortic valve 25 month follow up: no difference in progression of aortic valve calcification calcification or rate of increase in aortic jet velocityor rate of increase in aortic jet velocity

Medical TherapyMedical Therapy RAAVE Study: Rosuvastatin Affecting Aortic Valve Endothelium RAAVE Study: Rosuvastatin Affecting Aortic Valve Endothelium

(JACC 2007; 49(5): 554-61)(JACC 2007; 49(5): 554-61)NonrandomizedNonrandomizedProspectively assigned moderate to severe AS patients (AVA 1.0-1.5 cmProspectively assigned moderate to severe AS patients (AVA 1.0-1.5 cm22) ) to rosuvastatin 20 mg (61 patients with LDL>130 mg/dL) or no statin (60 to rosuvastatin 20 mg (61 patients with LDL>130 mg/dL) or no statin (60 patients with LDL<130 mg/dL)patients with LDL<130 mg/dL)Endpoints: aortic valve area, aortic jet velocityEndpoints: aortic valve area, aortic jet velocityRosuvastatin patients had significantly decreased rates of progression of Rosuvastatin patients had significantly decreased rates of progression of both endpoints (-0.05 vs. -0.10 cmboth endpoints (-0.05 vs. -0.10 cm22/year; +0.04 vs. +0.24 m/sec per year)/year; +0.04 vs. +0.24 m/sec per year)

SEAS Trial: Simvastatin and Ezetimibe in Aortic Stenosis SEAS Trial: Simvastatin and Ezetimibe in Aortic Stenosis (NEJM Sept 2, 2008)(NEJM Sept 2, 2008)1873 mild-moderate AS patients (peak aortic jet velocity 2.5-4 m/s)1873 mild-moderate AS patients (peak aortic jet velocity 2.5-4 m/s)Randomized to 40 mg simvastatin plus 10 mg ezetimibe (944 pts) vs. Randomized to 40 mg simvastatin plus 10 mg ezetimibe (944 pts) vs. placebo (949 pts)placebo (949 pts)Primary outcome: composite of major cardiovascular events (death from Primary outcome: composite of major cardiovascular events (death from cardiovascular causes, aortic-valve replacement, nonfatal MI, cardiovascular causes, aortic-valve replacement, nonfatal MI, hospitalization for unstable angina pectoris, heart failure, coronary-artery hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass CABG, PCI, and nonhemorrhagic stroke)bypass CABG, PCI, and nonhemorrhagic stroke)

SEAS--ResultsSEAS--Results

Aortic-valve replacement occurred in 267 patients (28.3%) in treatment group and in 278 patients (29.9%) in placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97)

Adverse EventsAdverse Events

Significantly increased incidence of cancersin simvastatin-ezetimibe group

SEAS—Conclusions SEAS—Conclusions Conclusions:Conclusions:

In patients with mild-to-moderate, asymptomatic In patients with mild-to-moderate, asymptomatic aortic-valve stenosis and no traditional indications for aortic-valve stenosis and no traditional indications for lipid-lowering therapy at baseline, long-term, lipid-lowering therapy at baseline, long-term, intensive lipid-lowering therapy with simvastatin and intensive lipid-lowering therapy with simvastatin and ezetimibe had no overall effect on the course of ezetimibe had no overall effect on the course of aortic-valve stenosisaortic-valve stenosis

Lipid-lowering therapy reduced risk of ischemic Lipid-lowering therapy reduced risk of ischemic cardiovascular events, especially the need for CABGcardiovascular events, especially the need for CABG

Higher incidence of cancer in the simvastatin–Higher incidence of cancer in the simvastatin–ezetimibe group requires further exploration in ezetimibe group requires further exploration in ongoing and future trials. ongoing and future trials.

Percutaneous Aortic Percutaneous Aortic ValveValve

First human case description 2002: 57-year-old man with calcific First human case description 2002: 57-year-old man with calcific aortic stenosis, cardiogenic shock, subacute leg ischemia, and aortic stenosis, cardiogenic shock, subacute leg ischemia, and other noncardiac diseases other noncardiac diseases Initially successful implant (transseptal approach)Initially successful implant (transseptal approach)Improved hemodynamicsImproved hemodynamicsPatient died of comorbid conditions 17 weeks after implantPatient died of comorbid conditions 17 weeks after implantCribier A, et al. Cribier A, et al. CirculationCirculation, Dec 2002; 106: 3006 – 3008, Dec 2002; 106: 3006 – 3008

Up to 500 patients worldwide have subsequently undergone Up to 500 patients worldwide have subsequently undergone implantationimplantation

Restricted to symptomatic severe AS patients with Restricted to symptomatic severe AS patients with contraindications for surgerycontraindications for surgery

May provide symptomatic relief for up to 2 yearsMay provide symptomatic relief for up to 2 years

Safety and long term durability remain in question Safety and long term durability remain in question Eur J Cardiothorac Surg 2008;34:1-8

Edwards SAPIENTM Percutaneous Valve

Equine pericardial trileaflet valve is sewn within a stainless steel frame. A fabric skirt covers the bottom third of the stent

23 and 26 mm diameter sizes14.5 and 16 mm height, respectively

Steerable deflection catheter used to guide prosthesis to aortic valve position

Percutaneous Aortic Percutaneous Aortic ValveValve

Rapid RV pacing reduces transvalvular pulsatile flow during device deployment

Webb, J. G. et al. Circulation 2006;113:842-850

Implantation OptionsImplantation Options

PARTNER TrialPARTNER Trial

Placement of AoRtic TraNscathetER Placement of AoRtic TraNscathetER ValvesValves

600 patient randomized controlled trial600 patient randomized controlled trial

PARTNER Trial: Inclusion PARTNER Trial: Inclusion CriteriaCriteria

Placement of AoRtic TraNscathetER ValvesPlacement of AoRtic TraNscathetER Valves

Inclusion Criteria: Cohort A (surgical AVR vs. transcatheter AVR): Inclusion Criteria: Cohort A (surgical AVR vs. transcatheter AVR): High Risk High Risk

1. Predicted operative mortality of 15% and a minimum STS score of 1. Predicted operative mortality of 15% and a minimum STS score of 10. 10.

2. Mean aortic gradient by TTE within 30 days of procedure>40mmHg 2. Mean aortic gradient by TTE within 30 days of procedure>40mmHg and/or jet velocity greater than 4.0 m/s or an initial aortic valve area and/or jet velocity greater than 4.0 m/s or an initial aortic valve area (AVA) of <0.8 cm2 (indexed EOA <0.5 cm2).(AVA) of <0.8 cm2 (indexed EOA <0.5 cm2).

3. NYHA Functional Class II or greater.3. NYHA Functional Class II or greater.

Cohort B (medical management including BAV vs. transcatheter Cohort B (medical management including BAV vs. transcatheter AVR): Extremely High RiskAVR): Extremely High Risk

1. All candidates for Cohort B of this study must meet # 2 and 3 1. All candidates for Cohort B of this study must meet # 2 and 3 above, andabove, and

2. The subject, after formal consults by a cardiologist and two 2. The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree that medical factors preclude cardiovascular surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful serious, irreversible morbidity exceeds the probability of meaningful improvement. Specifically, the probability of death or serious, improvement. Specifically, the probability of death or serious, irreversible morbidity should exceed 50%. irreversible morbidity should exceed 50%.

PARTNER Trial: Exclusion PARTNER Trial: Exclusion CriteriaCriteriaExclusion Criteria:Exclusion Criteria:

1. Acute MI 1month before intended treatment (defined as: STEMI, or NSTEMI with total CK 1. Acute MI 1month before intended treatment (defined as: STEMI, or NSTEMI with total CK elevation twice normal in the presence of MB elevation and/or troponin level elevation (WHO elevation twice normal in the presence of MB elevation and/or troponin level elevation (WHO definition).definition).

2. Congenital unicuspid or bicuspid aortic valve.2. Congenital unicuspid or bicuspid aortic valve.

3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic 3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+).regurgitation >3+).

4. Any therapeutic invasive cardiac procedure, other than BAV, performed within 30 days of the index 4. Any therapeutic invasive cardiac procedure, other than BAV, performed within 30 days of the index procedure, (or 6 months if the procedure was a drug eluting coronary stent implantation).procedure, (or 6 months if the procedure was a drug eluting coronary stent implantation).

5. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) 5. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency.mitral insufficiency.

6. Blood dyscrasias as defined: Leukopenia (WBC<3000 mm3), acute anemia (Hb< 9mg %), 6. Blood dyscrasias as defined: Leukopenia (WBC<3000 mm3), acute anemia (Hb< 9mg %), thrombocytopenia (platelet count <50,000 cells/mm³), history of bleeding diathesis or coagulopathy.thrombocytopenia (platelet count <50,000 cells/mm³), history of bleeding diathesis or coagulopathy.

7. Untreated clinically significant coronary artery disease requiring revascularization.7. Untreated clinically significant coronary artery disease requiring revascularization.

8. Hemodynamic instability requiring inotropic support or mechanical heart assistance.8. Hemodynamic instability requiring inotropic support or mechanical heart assistance.

9. Need for emergency surgery for any reason.9. Need for emergency surgery for any reason.

10. Hypertrophic cardiomyopathy with or without obstruction (HOCM).10. Hypertrophic cardiomyopathy with or without obstruction (HOCM).

11. Severe ventricular dysfunction with LVEF <20.11. Severe ventricular dysfunction with LVEF <20.

12. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.12. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.

13. Active peptic ulcer or upper GI bleeding within the prior 3 months.13. Active peptic ulcer or upper GI bleeding within the prior 3 months.

Exclusion CriteriaExclusion Criteria 14. Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or 14. Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or

clopidogrel (Plavix), or sensitivity to contrast media, which cannot be adequately pre-medicated.clopidogrel (Plavix), or sensitivity to contrast media, which cannot be adequately pre-medicated.

15. Native aortic annulus size < 16mm or > 24mm per the baseline echocardiogram as estimated 15. Native aortic annulus size < 16mm or > 24mm per the baseline echocardiogram as estimated by the left ventricular outflow tract (LVOT).by the left ventricular outflow tract (LVOT).

16. Patient has been offered but has refused surgery.16. Patient has been offered but has refused surgery.

17. Recent (within 6 months) cerebrovascular accident (CVA) or a transient ischemic attack (TIA).17. Recent (within 6 months) cerebrovascular accident (CVA) or a transient ischemic attack (TIA).

18. Renal insufficiency (Creatinine > 3.0) and/or end stage renal disease requiring chronic dialysis.18. Renal insufficiency (Creatinine > 3.0) and/or end stage renal disease requiring chronic dialysis.

19. Life expectancy < 12 months due to non-cardiac co-morbid conditions.19. Life expectancy < 12 months due to non-cardiac co-morbid conditions.

20. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal 20. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal luminal diameter 5cm or greater; marked tortuosity (hyper-acute bend), aortic arch atheroma luminal diameter 5cm or greater; marked tortuosity (hyper-acute bend), aortic arch atheroma (especially if thick [> 5 mm], protruding or ulcerated) or narrowing (especially with calcification (especially if thick [> 5 mm], protruding or ulcerated) or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta.the thoracic aorta.

21. Ileofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer 21. Ileofemoral vessel characteristics that would preclude safe placement of 22F or 24F introducer sheath such as severe obstructive calcification, severe tortuosity or vessels size less than 7 mm in sheath such as severe obstructive calcification, severe tortuosity or vessels size less than 7 mm in diameter.diameter.

22. Currently participating in an investigational drug or another device study. [Note: Trials 22. Currently participating in an investigational drug or another device study. [Note: Trials requiring extended follow-up for products that were investigational, but have since become requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials].commercially available, are not considered investigational trials].