Amit J. Thosani 10 September 2008

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 285-288.

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 • Aortic medial thickening/ • disorganization cause • constricting annular ridge • superior to sinuses of • Valsalva • Most common subtype Hourglass http://img.tfd.com/mosbycam/thumbs/500227-fx36.jpg • 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 www.med.yale.edu • 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 http://phil.cdc.gov/PHIL_Images/02051999/00014/20G0014_lores.jpg

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, 2004. pp. 278.

18. 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. 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/1.45 + 2 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 2006 AHA/ACC Guidelines Otto CM, Burwash IG, Legget ME, et al. Circulation 1997; 95:2262-2270.

25. Evaluation of AS Severity

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); 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

32. 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)

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;113:842-850

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 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].