1. Aortic Stenosis
Amit J. Thosani
10 September 2008

2. Epidemiology Common due to:
Aging population—3-5% prevalence in population >75
Relatively common incidence of bicuspid AoV (1-2% of population)
Long latent period, asymptomatic progression from AVA 3-4 cm2 to 1.5 cm2
Additional reduction in valve area from ½ to ¼ normal size usually results in symptoms

3. Pathophysiology Outflow obstruction results in:
Concentric hypertrophy in response to increased LV pressures to maintain normal wall stress; initially preserved LVEDV and CO
With increasing afterload from increasing obstruction, further hypertrophy results in:
--increased O2 demand
--decreased coronary perfusion pressure
--intramyocardial arterial compression
--interstitial fibrosis and diastolic dysfunction
Ultimately resulting in myocardial ischemia and reduced contractility
Angina secondary to above
Dyspnea due to diastolic dysfunction and inadequate cardiac output in setting of fixed obstruction
Dizziness/syncope due to exercise induced vasodilation in setting of fixed output, baroreceptor abnormalities, arrhythmia (AF)
Heart failure: advanced disease, low output state

4. Progression of AS
Mean pressure gradient increase up to 10 mm Hg/year (mean 7 mm Hg)
Aortic valve area decrease of 0.12 ± 0.19 cm2/year
Individual variability exists
Feigenbaum’s Echocardiography, Sixth Edition, 2005, pp

5. Natural History Prognosis significantly worsens with onset of symptoms
Average survival with symptom onset: less than 2-3 years
Increased risk of sudden death

6. Etiologies Nonvalvular: Subaortic Supravalvular Valvular:
Calcific (7th or 8th decade)
Bicuspid (4th or 5th decade)
Rheumatic: more common in developing nations

7. Subaortic Stenosis Fixed vs. Dynamic (HOCM)
Distinct morphologies of fixed obstruction:
--Thin membrane (most common): typically seen proximal to aortic root/septum junction
--Thick fibromuscular ridge
--LVOT hypoplasia
Often associated with AR
Pathophysiology: LVOT abnormalities causing LVOT obstruction/fibrosis, LV hypertrophy, hyperdynamic function

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

9. Supravalvular AS: Etiologies
4 distinct inheritance patterns:
Williams Syndrome: “elfin facies,” mental retardation, hypercalcemia, failure to thrive, renovascular hypertension, short stature
Likely autosomal dominant inheritance; may be related to elastin gene mutation (chromosome 7q11.23)
Autosomal dominant familial form (without features of Williams Syndrome)
Sporadic form without family history
Homozygous familial hypercholesterolemia (FH):
Autosomal dominant disorder; up to 44% have supravalvar AS
Less frequent in heterozygotes, typically affecting adults

10. Supravalvular AS: Morphologies
Hourglass
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

11. Supravalvular AS

12. Supravalvular AS TEE Aortgraphy Surgical repair is definitive therapy
Usually performed at lower gradient levels than in valvular AS to prevent long term sequellae
Outcomes better for focal disease than diffuse hypoplasia
Youn, HJ, Chung, WS, Hong, SJ. Heart 2002; 88:438.

13. Valvular AS: Etiologies
Normal Aortic Valve
Congenital Bicuspid Aortic Valve
Rheumatic Aortic Valve
Calcific Aortic Valve
Braunwauld’s Heart Disease

14. Congenital Valvular AS: Unicuspid and Bicuspid
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
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.

15. Rheumatic AS Fusion of commissures and cusps
Leaflet vascularization, causing stiffening of cusps free borders
Typically regurgitant and stenotic
Rheumatic mitral disease nearly always present in patients with rheumatic AS

16. Calcific AS
Disease process likely similar to vascular atherosclerosis: inflammatory and proliferative changes
Risk Factors:
1. Age
2. Elevated LDL and Lp(a)
3. Diabetes
4. Hypertension
5. Cigarette smoking
Cytokine release by infiltrating T-lymphocytes and macrophages promotes:
1. Extracellular matrix remodelling
2. Cellular proliferation
3. Differentiation of subset of fibroblasts into myofibroblasts possessing smooth muscle cell properties
4. Lipid accumulation (LDL, oxidized by macrophages)
5. Subset of myofibroblasts differentiate into an osteoblast phenotype, capable of calcium nodules and bone formation
Freeman RV, Otto CM. Circulation 111: 3316, 2005.

17. AS: Fluid Dynamics
Laminar 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, pp. 278.

18. ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v)
AS: Fluid Dynamics
Pressure gradient across stenotic valve is related to velocity in the jet, first described by Bernoulli in 1738, later refined by Euler, first applied to stenotic aortic valves by Hatle in 1979:
ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v)
ΔP Pressure gradient across valve (mm Hg)
p Mass density of blood (1.06 x 103 kg/m3)
v2 Velocity in stenotic jet
v1 Velocity proximal to stenosis
(dv/dt)dx Time-varying velocity at each distance along flowstream
R(v) Constant for viscous resistance

19. ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v)
Modified Bernoulli
ΔP = ½ p (v22- v12) + p (dv/dt)dx + R(v)
Eliminating terms for viscous losses and acceleration, using known values for mass density of blood, and converting velocity to m/s yields modified Bernoulli equation:
ΔP = 4(v22- v12)
If proximal velocity is < 1 m/s, modified Bernoulli is further simplified:
ΔP = 4v2

20. Mean Pressure Gradient
ΔPmean = ΔPmax/ mm Hg
Mean gradient is approximately 2/3 of the peak instantaneous gradient

21. Calculation of AVA Planimetry Gorlin Equation
AVA=(CO)/(HR)(SEP)(44.3)(√mean gradient)
Hakki Equation (simplfication of Gorlin)
AVA=(CO)/(√peak gradient)
Continuity Equation

22. AVA Calculation: Echocardiography vs. Invasive Hemodynamics
Peak 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

23. Continuity Equation SVLVOT=SVAo CSALVOT x VTILVOT = CSAAo x VTIAo
AVA = (CSALVOT x VTILVOT )/VTIAo
LVOT diameter: Parasternal Long Axis
VTILVOT: 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

24. Evaluation of AS Severity
Maximal Aortic Valve Velocity:
In asymptomatic AS patients, AoV velocity is strongest predictor of outcomes:
≤3 m/s: death or AVR 8%/year
3-4 m/s: 17% per year
≥4 m/s: 40% per year
Vmax (m/s)
Severity ≥4
Severe
3-4
Moderate
1.6-3
Mild
≤ 1.5
Normal
2006 AHA/ACC Guidelines
Otto CM, Burwash IG, Legget ME, et al. Circulation 1997; 95:

25. Evaluation of AS Severity
Mean Gradient (mmHg)
AVA (ACC/AHA) (cm2)
AVA (BIDMC)
(cm2)
Normal
<5
3-4
Mild
<25
>1.5
>1.2
Moderate
25-40
Severe
>40
<1.0
<0.8

26. Imaging Challenges Parallel intercept angle between ultrasound beam
and aortic jet ensures maximal measured Ao velocity,
as cos θ =1.
Deviation from parallel underestimates jet velocity,
which is squared in continuity equation, magnifying
the 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 regurgitation
Tricuspid regurgitation
VSD
Pulmonic stenosis

27. Imaging Challenges
LV outflow diameter measurement critical to accurate calculation of AVA
Arrhythmia: variability in velocity depending on stroke volume and preceding R-R interval

28. Challenges: Low Gradient AS
Definition: Severe AS (AVA<1.0 cm2) with transvalvular pressure gradient <30 mm Hg
Challenge is to differentiate low gradient AS patients who will benefit from AVR (“true stenosis”) from those who will not
“Psedostenosis:” symptoms due primarily to LV dysfunction rather than valvular disease
Gorlin and Hakki equations underestimate AVA when CO is low

29. Challenges: Low Gradient AS
AS Assessment with LV Dysfunction

30. Therapy Surgical AVR is mainstay of treatment
ACC/AHA Class IA Indications:
Symptomatic severe AS
Severe AS in patients undergoing CABG, aortic, or other heart valve surgery
Severe AS with LVEF less than 50%
Class IIA Indications:
Moderate AS in patients undergoing CABG, aortic, or other heart valve surgery
Class IIB
Severe 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

31. Medical Therapy Association between AS progression and dyslipidemia
Pohle K, Maffert R, Ropers D, et al. Circulation 2001; 104(16);
AS calcification and progression increased in patients with serum LDL>130 mg/dL
SALTIRE Trial: Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (NEJM 2005; 352(23): )
155 calcific AS patients (aortic jet velocity>2.5 m/s, calcification seen on TTE, mean AVA 1.03 cm2)
Randomized to atorvastatin 80 mg vs. placebo
Nonclinical endpoints: change in aortic jet velocity and aortic valve calcium score
25 month follow up: no difference in progression of aortic valve calcification
or rate of increase in aortic jet velocity

32. Medical Therapy
RAAVE Study: Rosuvastatin Affecting Aortic Valve Endothelium
(JACC 2007; 49(5): )
Nonrandomized
Prospectively assigned moderate to severe AS patients (AVA cm2) to rosuvastatin 20 mg (61 patients with LDL>130 mg/dL) or no statin (60 patients with LDL<130 mg/dL)
Endpoints: aortic valve area, aortic jet velocity
Rosuvastatin patients had significantly decreased rates of progression of both endpoints (-0.05 vs cm2/year; vs m/sec per year)
SEAS Trial: Simvastatin and Ezetimibe in Aortic Stenosis
(NEJM Sept 2, 2008)
1873 mild-moderate AS patients (peak aortic jet velocity m/s)
Randomized to 40 mg simvastatin plus 10 mg ezetimibe (944 pts) vs. placebo (949 pts)
Primary outcome: composite of major cardiovascular events (death from cardiovascular causes, aortic-valve replacement, nonfatal MI, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass CABG, PCI, and nonhemorrhagic stroke)

33. SEAS--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)

35. Adverse Events Significantly increased incidence of cancers
in simvastatin-ezetimibe group

36. SEAS—Conclusions Conclusions:
In patients with mild-to-moderate, asymptomatic aortic-valve stenosis and no traditional indications for lipid-lowering therapy at baseline, long-term, intensive lipid-lowering therapy with simvastatin and ezetimibe had no overall effect on the course of aortic-valve stenosis
Lipid-lowering therapy reduced risk of ischemic cardiovascular events, especially the need for CABG
Higher incidence of cancer in the simvastatin–ezetimibe group requires further exploration in ongoing and future trials.

37. Percutaneous Aortic Valve
First human case description 2002: 57-year-old man with calcific aortic stenosis, cardiogenic shock, subacute leg ischemia, and other noncardiac diseases
Initially successful implant (transseptal approach)
Improved hemodynamics
Patient died of comorbid conditions 17 weeks after implant
Cribier A, et al. Circulation, Dec 2002; 106: 3006 – 3008
Up to 500 patients worldwide have subsequently undergone implantation
Restricted to symptomatic severe AS patients with contraindications for surgery
May provide symptomatic relief for up to 2 years
Safety and long term durability remain in question
Eur J Cardiothorac Surg 2008;34:1-8

38. 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 sizes
14.5 and 16 mm height, respectively
Steerable deflection catheter used to guide prosthesis to aortic valve position

39. Percutaneous Aortic Valve
Rapid RV pacing reduces transvalvular pulsatile flow during device deployment
Webb, J. G. et al. Circulation 2006;113:

40. Implantation Options

41. PARTNER Trial Placement of AoRtic TraNscathetER Valves
600 patient randomized controlled trial

42. PARTNER Trial: Inclusion Criteria
Placement of AoRtic TraNscathetER Valves
Inclusion Criteria: Cohort A (surgical AVR vs. transcatheter AVR): High Risk
1. Predicted operative mortality of 15% and a minimum STS score of 10.
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 (AVA) of <0.8 cm2 (indexed EOA <0.5 cm2).
3. NYHA Functional Class II or greater.
Cohort B (medical management including BAV vs. transcatheter AVR): Extremely High Risk
1. All candidates for Cohort B of this study must meet # 2 and 3 above, and
2. The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement. Specifically, the probability of death or serious, irreversible morbidity should exceed 50%.

43. PARTNER Trial: Exclusion Criteria
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 definition).
2. Congenital unicuspid or bicuspid aortic valve.
3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation >3+).
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).
5. Pre-existing prosthetic heart valve in any position, prosthetic ring, or severe (greater than 3+) mitral insufficiency.
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.
7. Untreated clinically significant coronary artery disease requiring revascularization.
8. Hemodynamic instability requiring inotropic support or mechanical heart assistance.
9. Need for emergency surgery for any reason.
10. Hypertrophic cardiomyopathy with or without obstruction (HOCM).
11. Severe ventricular dysfunction with LVEF <20.
12. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.
13. Active peptic ulcer or upper GI bleeding within the prior 3 months.

44. Exclusion Criteria
14. Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or 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 by the left ventricular outflow tract (LVOT).
16. Patient has been offered but has refused surgery.
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.
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 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 and surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the thoracic aorta.
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 diameter.
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 commercially available, are not considered investigational trials].