Download 9/08 Aortic Stenosis

Aortic Stenosis
Amit J. Thosani
10 September 2008
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
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
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 285-288.
Natural History
Prognosis significantly worsens with onset of symptoms
Average survival with symptom onset: less than 2-3 years
Increased risk of sudden death
Etiologies

Nonvalvular:
Subaortic
Supravalvular

Valvular:
Calcific (7th or 8th decade)
Bicuspid (4th or 5th decade)
Rheumatic: more common in developing nations
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
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.
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
Supravalvular AS: Morphologies
Hourglass
•Aortic medial thickening/
disorganization cause
constricting annular ridge
superior to sinuses of
Valsalva
•Most common subtype
http://img.tfd.com/mosbycam/th
umbs/500227-fx36.jpg
Membranous: fibrous/fibromuscular diaphragm with small opening
stretched across aorta
Diffuse Hypoplasia
Supravalvular AS
Supravalvular AS
TEE
Aortgraph
y
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.
Valvular AS: Etiologies
A. Normal Aortic Valve
B. Congenital Bicuspid
Aortic Valve
C. Rheumatic Aortic
Valve
D. Calcific Aortic Valve
Braunwauld’s Heart Disease
Congenital Valvular AS: Unicuspid and
Bicuspid
www.med.yale.edu
Bicuspid Aortic Valve:
•Typically normal function in childhood
•May cause severe obstruction in infancy
•Aortic stenosis presentation after 50
years of age
•Male:female 4:1
•20% develop aortic regurgitation between
•Associated with coarctation, PDA
ages 10-40, may require AVR
•Most common cause of fatal AS <1yr of age •Increased risk of endocarditis
•Associated with dilated ascending aorta
Unicuspid Aortic Valve:
Lewin MB, Otto CM. Circulation 111: 832, 2005.
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
http://phil.cdc.gov/PHIL_Images/02051999/00014/20G0014_lores.jpg
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.
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, 2004. pp. 278.
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
p
v2
v1
(dv/dt)dx
R(v)
Pressure gradient across valve (mm Hg)
Mass density of blood (1.06 x 103 kg/m3)
Velocity in stenotic jet
Velocity proximal to stenosis
Time-varying velocity at each distance along flowstream
Constant for viscous resistance
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
Mean Pressure Gradient
ΔPmean = ΔPmax/1.45 + 2 mm Hg
Mean gradient is approximately 2/3 of the peak
instantaneous gradient
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
AVA Calculation: Echocardiography
vs. Invasive Hemodynamics
Peak aortic and left ventricular
pressures do not occur
simultaneously
Maximum instantaneous
gradient is greater than peak-topeak gradient
Echocardiography and cardiac
catheterization may yield
discrepant results
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
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
Otto CM, Burwash IG, Legget ME, et al. Circulation 1997; 95:2262-2270.
Vmax (m/s) Severity
≥4
Severe
3-4
Moderate
1.6-3
Mild
≤ 1.5
Normal
2006 AHA/ACC Guidelines
Evaluation of AS Severity
Severity
Mean
Gradient
(mmHg)
AVA
(ACC/AHA)
(cm2)
AVA
(BIDMC)
(cm2)
Normal
<5
3-4
Mild
<25
>1.5
>1.2
Moderate
25-40
1.0-1.5
0.8-1.2
Severe
>40
<1.0
<0.8
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
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
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
Challenges: Low Gradient AS
AS Assessment with LV Dysfunction
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
Medical Therapy

Association between AS progression and dyslipidemia
Pohle K, Maffert R, Ropers D, et al. Circulation 2001; 104(16); 1927-32.

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): 2389-97)
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
Medical Therapy

RAAVE Study: Rosuvastatin Affecting Aortic Valve Endothelium
(JACC 2007; 49(5): 554-61)
Nonrandomized
Prospectively assigned moderate to severe AS patients (AVA 1.0-1.5 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.
-0.10 cm2/year; +0.04 vs. +0.24 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 2.5-4 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)
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)
Adverse Events
Significantly increased incidence of cancers
in simvastatin-ezetimibe group
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.
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
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
Percutaneous Aortic Valve
Rapid RV pacing reduces transvalvular
pulsatile flow during device deployment
Webb, J. G. et al. Circulation 2006;113:842-850
Implantation Options
PARTNER Trial


Placement of AoRtic TraNscathetER Valves
600 patient randomized controlled trial
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%.
PARTNER Trial: Exclusion Criteria
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.
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].