What Determines the Outcome of Aortic Stenosis?

Transcription

1 What Determines the Outcome of Aortic Stenosis? Jutta Bergler-Klein Assoc. Professor of Medicine Dept of Cardiology, Med. Univ. Vienna meduniwien.ac.at

2 AS in Perspective AS most common valvular disease in Europe and USA, 2 nd most common cardiac entity Increasing with age Degenerative vs bicuspid / congenital

3 Survival, % Symptoms and Outcome Natural History of Severe AS Symptoms mark critical obstruction rapid AVR - subtle, not recognized, in elderly pts, comorbidities - Risk of sudden death / Op. risk, prosthesis complications Careful history, change in ex. capacity? risk stratification Latent period (Increasing obstruction) Symptoms onset Heart failure syncope angina Mean survival (years) Age Ross, Braunwald. Circulation 1968

4 Severity of AS: Determinant of Outcome Echo, Doppler as standard: AV Vel most important parameter, adequate window, CW probes Mean gradient AVA (continuity equation) Look at the valve: anatomy, calcification EAE / ASE Recommendations. Baumgartner, Hung, Otto et al. JASE 2009 Otto C. J Am Coll Cardiol 2006; 47

5 Symptom free Survival and AV-Velocity Over 2 y, up to 80% pts with AV Vel >4 develop symptoms compared to 15% < 3 m/s AV Vel > fold > likelihood of developing symptoms, 1.5-fold surgery / death vs Vel m/s (n=622) N=123 N=183 Otto C et al. Circulation 1997 Pellikka P, Sarano ME, Circulation 2005 Stewart R, Kerr A, Eur Heart J 2010; June

6 Overlap of AV-Velocity and AVA in Determining Outcome in Asympt. AS Substantial overlap in pts developing symptoms, or death No specific value, variable outcome Otto C, Circulation 1997; 95 Carabello B, Lancet 2009; 373

7 Valve Calcification in AS Event-free survival (death, AVR) signif. related to calcification Rapid progression AV-Vel 0.3 m/s per year and severe calcification high risk subgroup CT Scan only in unclear cases e.g. low flow AS, Agatston Score>1651 N=25 P< Visual calcification score, echo N=126, asympt. severe AS, mean FU 22 months N=101 Rosenhek R, Binder T, Porenta G, Maurer G et al. N Engl J Med 2000; 343 Messika-Zeitoun D, Circulation 2004; 110

8 Severity of AS with normal LV Function AHA /ACC and *ESC Guidelines Mild Moderate Severe AVA cm Indexed cm 2 /m Mean Grad mmhg Peak Velocity m/sec (50*) > 40 (50*) > 4 * As long as MG still >40 virtually no lower EF limit for OP * ESC Guidelines. Eur Heart 2007; 28 ACC/ AHA Guidelines Valv. Heart Disease. Circulation 2006 and 2008

9 Very Severe Asympt. AS: Role of AV Velocity AV-Vel >5-5.5 m/s predicts very poor outcome in asympt. AS Superior to AVA > or < 0.6 cm² n.s. N=116, AV-Vel 5 AVA 0.63±0.12 AV-Vel 5.37±0.35

10 Gradient Across Stenotic Aortic Valve Determined by Stroke volume Duration of systolic ejection time per beat dependent on Myocardial contractility LV pre-load LV afterload Systolic pressure in ascending aorta Rahimtoola SH. JACC Cardiovasc Imaging. 2010; 3(6) Dumesnil JG, Carabello B, Pibarot P, Eur Heart 2009

11 Role of Flow and Gradients Severe AS: A New Classification? Severe AS with high gradients (AVA<1, MG>40) AVR usually beneficial outcome - Normal Flow AS with normal EF - Normal Flow AS with reduced EF Severe AS with low gradients (AVA<1, MG<40) Clinical dilemma - OP? - Low Flow Low Gradient AS with reduced EF - Low Flow AS Low Gradient AS with normal EF Paradoxical Low Flow AS

12 Inconsistencies of Echo Criteria Grading of AS Severity 30% pts inconsistent grading vs lower SV AVA<1 despite MG<40. Guidelines Severe AS AVA< 1 MG >40 (50) AV Vel >4 ESC: Severe AS unlikely if MG <50 N=2427 normal EF Minners J, Allgeier M, Gohlke-Bärwolf C et al. Eur Heart 2008; 29: Flachskampf F. Eur Heart 2008; 29:966

13 Which Determinants in Asympt. AS? Obstruction Severity vs Physiol. Consequences AS Severity Arterial afterload RR BNP Systolic Diastolic LVF Bergler-Klein, ESC 2010 Adapted from: Pellikka P. Eur Heart 2010; June 17

14 What determines the outcome in AS? Severity of obstruction - AV-Velocity, gradients, valve area - Calcification amount Pathophysiological consequences - LVH, LV mass, myocardial fibrosis - Diastolic dysfunction, LA dilatation - Systolic LV function: EF, TDI, strain - BNP release Other factors - Age, gender - Comorbidities (renal failure, diabetes, CAD ) - Metabolic, atherosclerotic factors, inflammation - Postop.: prosthesis related, mismatch, LVF Combination of determinants

15 Concentric Remodeling in AS Small LV ejects small SV low gradients High prevalence (up to 30%) severe AS with reduced SV despite EF >50%: Paradox. low flow AS Courtesy of P. Pibarot, Quebec, TOPAS Hachicha Z, Dumesnil J, Pibarot P, Circulation 2007;115 Cramariuc D, Gerdts E, SEAS, JACC img 2009; 2

16 Concept of Global LV Afterload in AS Valvular component (gradient, severity of stenosis) Arterial resistance : atherosclerotic continuum Hypertension >50% of pts, measure RR at echo Valvulo-arterial Impedance Zva Zva= RR systol + MG SVI Mortality in Asympt AS >3.5, Paradox >5.5 mmhg/ml/m 2 Dumesnil J, Pibarot P, Carabello B. Eur Heart 2009 Sept 8; Hachicha Z, Dumesnil, Pibarot. JACC 2009; 54 Barasch E et al. J Heart Valve Dis 2008; 17

17 Paradoxical Low Flow Low Gradient AS Severe AS despite Low Gradient Poor outcome without OP AVAi <0.6, EF 50 Low SVI 35 Low MG 32± Overall Survival % AVR AVR performed % 65 % NF 47 % PLF Hachicha Z, Dumesnil JG, Pibarot P et al. Circulation p< N=512 No AVR years 4 5 Normal Flow AS: SVI >35 ml/m² Paradox Low Flow AS: SVI 35, 35% pts

18 LV Hypertrophy and Mass - A double-edged sword? Pressure overload adaptive concentric LVH, preserving EF Fibrosis, impaired coronary flow, ischemia, filling pressures Diastolic, systolic LV dysfunction, strain, SV, EF Global afterload - valvular and arterial determinants hypertension (often eccentric geometry) Genetic factors in LVH pattern, geometry LVH impacts outcome in AS, sudden death risk Carabello B, Paulus W. Lancet 2009; 373 Cramariuc D, Gerdts E et al. Heart 2010; 96 Pellikka P, Sarano ME et al. Circulation. 2005;111 Rossebo A, SEAS, ESC 2010

19 Impact of Myocardial Fibrosis in AS High degree of replacement fibrosis in MRI (late enhancement) - Higher NT-proBNP (median 2043 vs 377 pg/ml, no fibrosis) - Reduced longit. strain (echo) despite normal EF Worse outcome and myocardial function after AVR N=58 symptom. severe AS MRI well related to intraop. biopsies Weidemann F, et al. Circulation 2009; 120:577-84

20 LV Mass predicts Sudden Death in Mild to Moderate AS: SEAS substudy No signif. difference in baseline RR, AV gradients, EF, independent of hypertension AS, No SD N=1687 Sudden Death N=35 Septum, enddiastolic (cm) 1.16± ± Posterior wall, enddiastolic cm 0.89± ± LVDd (cm) 5.03± ± LV Mass (g) 193.6± ± RWT 0.36± ± Rossebo A, Gohlke-Bärwolf C, Boman K, Chambers J, Gerdts E, Holme I, Ray S, Wachtell K, Willenheimer R, Pedersen T. ESC 2010 P

21 Risk of Sudden Death in Mild to Moderate AS: SEAS substudy N=1873 asympt. AS, AV Vel 2-4m/s, mean 3.09, FU 52.2 mo, age 68y mean 2.1% Sudden Death (n=40), Incidence 0.37% per year Predictors: Posterior wall thickness p=0.006, HR 1.55 ( ) LV Mass p< 0.001, HR 1.61 ( ) LV Mass index, p<0.001 MG p=0.049, HR 1.37 ( ), AVA n.s. No clinical or lab / chemistry values predictive LV mass stronger predictor of SD than AS severity. Moderate AS not a benign disease. Rossebo A, Gohlke-Bärwolf C, Boman K, Chambers J, Gerdts E, Holme I, Ray S, Wachtell K, Willenheimer R, Pedersen T. ESC 2010

22 Sudden Death in Asympt. AS Small, still significant risk 1% not well predicted by severity of AS OP risk 2-5%, depending on comorbidities, age SD risk increases highly with onset of symptoms importance of identifying symptoms Role of exercise testing? 5% SD in 1y with abnormal test vs 0% normal, metaanalysis N=491 Pellikka P, Sarano ME, Nishimura R et al. Circulation. 2005;111 Rafique A, Biner S, Ray I et al. Am J Cardiol 2009;104 Vahanian A, Otto C. Eur Heart J 2010; 31

23 Exercise Test in Asympt. AS Current guidelines recommend surgery in asympt. severe AS in pts exhibiting exercise-limiting symptoms (ESC Class Ic; ACC/AHA IIb) fall in blood pressure (ESC IIa, ACC/AHA IIb) complex ventricular arrhythmias (ESC IIb) during exercise Vahanian A et al. Eur Heart J 2007;28 Bonow RO et al. J Am Coll Cardiol 2008;52 Amato M, Hoffmann J, Fournet P, Heart 2001; 86 Das P, Rimington H, Chambers J. Eur Heart J 2005;26

24 Exercise Stress Echo in True Asympt. AS Exercise increase in MG >20 mmhg poor outcome even in asympt. pts with normal exercise test Other predictors: MG rest >35, p< LV Hypertrophy p<0.01 Age >65, p<0.01 Diabetes p<0.01 N=135 >moderate AS normal EF 50% events (67 pts) * Marechaux S, Hachicha Z, Dumesnil J, Pibarot P et al. Eur Heart J 2010; 31 Lancellotti P, Pierard Let al, Circulation 2005;112(Suppl)

25 LV Mass Predicts Morbidity and Mortality in Mild/ Moderate AS: SEAS substudy N=1730 asympt. AS, AV-Vel (3.09±0.54), age 67±10, FU 4.3y, 173 centers Europe (simvastatin/ ezetimibe vs plac) Predictors: LV mass index : p<0.01 (HR 1.18 ( ), 31 g/m² =1 SD) 15-28% events, independent of AS severity, age, RR AV-Velocity: p<0.01 (HR 1.93 ( ), 0.54 m/s =1 SD) LV mass predicts mortality and event rate in AS Strong determinant in moderate asympt. AS independent of AS severity or hypertension. Gerdts E, Cramariuc D, Lonnebakken M, Rieck A, Lund B, Devereux R. ESC 2010

26 LV Mass and Aortic Valve Events SEAS substudy Signif. higher event rate with higher LV mass, p<0.001, independent of AS severity or hypertension N=1730, mild/mod AS FU 4.3y 606 Major CV events 560 Aortic valve events 296 Ischemic events Gerdts E, Cramariuc D, Lonnebakken M, Rieck A, Lund B, Devereux R, ESC 2010

27 Myocardial Deformation in Relation to LV Geometry in AS Longit. Strain signif. reduced in concentric hypertrophy Early myocardial deterioration in increased LV mass N=70 age 73±10 AVAi 0.56± ±3 Cramariuc D, Gerdts E et al. Heart 2010 ; 96:

28 - GLPSS % 2D Strain and NT-proBNP: Predictors of Outcome in Severe AS? Despite preserved EF early LV deterioriation Longit. strain -13 % and NT-BNP >800 predict need for AVR within 6-12 months in severe asympt. AS r=-0.62 p< NT-proBNP pg/ml Mean GLPSS -15 ±3 % N=28 AVA 0.67±0.16 Bergler-Klein J, Rosenhek R, Maurer G, Binder T et al. ACC 2010

29 Predictors in Asympt. Severe AS AV Velocity Valvulo-arterial impedance 2D Longit. Strain LA size LA size: diastolic burden Lancellotti P, Donal E, Magne J et al. Heart 2010 May

30 Why is BNP increased in AS? BNP and Myocardial Wall Stress Diastolic stretch induces BNP expression in myocyte Volume overload - CHF, AR. Pressure overload - AS CHF pts Symptomatic AS Iwanaga et al. JACC 2006; 47 (4) Vanderheyden M; JACC 2004; 2349

31 BNP related to Severity of AS Normal Flow BNP r NT-proBNP r NT-proANP r AVA Peak Vel MG LA LV Mass Index LV EF Gerber I et al. Circulation 2003; 107; Bergler-Klein, Circulation 2004 Weber M, Eur Heart J 2005; 26: Qi W, Am Heart J. 2001;142:

32 Symptom Free Survival Symptom Free Survival Symptom-Free Survival in Asympt. AS NT-pro/ BNP 100% 1 100% 1 80,8 60,6 40,4 20,2 0 0 BNP < 130 pg/ml BNP 130 p< ,8 60,6 BNP <130 pg/ml p< BNP >=130 pg/ml,4 NT-BNP < 80 pmol/l 20,2 NT-BNP pg/ml Follow-up Days Days Follow-up Days Days Bergler-Klein et al, Circulation 2004; 109

33 BNP predicts Postop Outcome NT- / BNP significantly higher in pts who died postop* Preop. BNP and Euroscore related in sympt. AS BNP >312 pg/ml superior in predicting postop outcome N=144 r = p<0.001 Pedrazzini G, Masson S, Latini R et al. Am J Cardiol 2008; 102 * Bergler-Klein J, Baumgartner H et al. Circulation 2004

34 Risk Score for Asymptom. AS with BNP Independent Predictors of Outcome N=107 Odds ratio 95% confidence interval p Baseline BNP Baseline Peak Velocity Female gender Interplay of valve obstruction and LV function RISK SCORE: [Peak velocity (m/s) x 2] + [natural Log BNP x 1.5] +1.5 (female) Monin JL, Lancellotti P et al. Circulation 2009; 120:69-75

35 BNP for Risk Stratification in Low Flow AS: Beyond Contractile Reserve No CR: survival poor only when BNP 550 TAVI? Pts without CR and low BNP better outcome AVR. Multicenter TOPAS Low Flow AS AVA ind <0.6 MG< 40 EF< 40. p=0.002 Low flow Low Gradient AS Quebec, Ottawa, Münster, Vienna Bergler-Klein, Mundigler, Pibarot, Baumgartner et al. Circulation 2007; 115

36 Low flow Low Gradient AS (Low EF): Survival without CR after AVR 81 pts without CR (SV <20%), AVA 0.75± 0.16, EF 29 ±7%, age 71±10 y better longterm survival with AVR, but high OP mortality OP mortality 22% 5y Survival AVR 54 ±7 % Medical 13±7 Tribouilly C, Levy F, Monin JL, JACC 2009; 53:

37 Parameters of Survival in Low Flow Low Gradient AS (Low EF) Lack of contractile reserve (DSE SV>20%, EF>20%, flow) High BNP Low functional capacity (6 min walk) Projected valve area (true vs pseudosevere AS, TOPAS) Low preop. MG < 20 Severe CAD/ scars Atrial fibrillation, arrhythmias Comorbidities, renal failure, COPD,. Prosthesis mismatch Consider TAVI in high risk pts Clavel, Burwash, Mundigler, Dumesnil, Baumgartner, Bergler-Klein, Pibarot, Circulation 2008 Tribouilly C, Levy F, Monin, JACC 2009 Levy, Monin, J Am Coll Cardiol 2008 Clavel, Burwash, Mundigler, Dumesnil, Baumgartner, Bergler-Klein, Pibarot, JASE 2010

38 What influences Progression of AS? Factors in Development of Calcific AS External factors Comorbidities Metabolic syndrome Rajamannan N, Arterioscler Thromb Vasc Biol. 2009;29

39 Metabol. Syndrome and AS Progression: Influence of Age Faster progression in younger pts with MetS: different mechanisms of progression? Visceral obesity new therapeutic target in young? 243 pts ASTRONOMER Capoulade R, Clavel MA, Dumesnil JG, Chan K, Teo K, Tam J, Mathieu P, Despres J, Pibarot P. ESC 2010

40 Metabolic Syndrome Predicts Faster Progression of AS: ASTRONOMER Prospective 243 pts, mild-moderate AS, AV Vel , multicenter Canada ( rosuvastatin 40 mg vs plac), FU 3.4 ±1.3y 26% with MetS (63 pts): AV Vel faster increase: p=0.03, 0.26±0.02 vs 0.19±0.01 m/s year Multivariate predictors of progression: AV Vel p=0.005 Calcification p=0.006 MetS p=0.009 Age >57 p=0.01 MetS strong predictor of progression Capoulade R, Clavel MA, Dumesnil JG, Chan K, Teo K, Tam J, Mathieu P, Despres J, Pibarot P. ESC 2010

41 Impaired LV Function and Geometry in Metabol. Syndr. in AS (ASTRONOMER) MetS: more concentric LVH, LV mass reduced intrinsic myocardial function (tissue doppler) Common pathway of MetS, AS progression, LVH, LVF and outcome? 272 pts, mild-moderate AS, AV Vel Pagé A, Dumesnil J, Clavel MA, Chan K, Pibarot P, JACC 2010:

42 Bicuspid Aortic valve 1-2 % of newborn with bicuspid valve, more males May be undiagnosed until adult life AS in bicuspid valves 2 decades earlier than in tricuspid Risk of aortic dissection Siu S, Silversides C. J Am Coll Cardiol 2010; 55 Farasat M. JACC 2010; 55 (7) Baumgartner H, Bonhoeffer P, De Groot NM, GUCH guidelines Eur Heart J 2010, Aug Warnes C, Williams R, Bashore T et al. JACC 2008;52

43 Bicuspid Aortic Valve: A Syndrome Valvular and Aortic disease: aortic root, ascendens, Structural disorders of aortic media at cellular level: fibrillin, elastin matrix metalloproteinases matrix disruption, smooth muscle cell loss Genetic factors (NOTCH-1, mutations ) BAV in up to 24% of family members, prevalence 9% in 1 st degree relatives screening Siu S, Silversides C. JACC 2010; 55 Bonderman D, Wollenek G, Lang I, Circulation 1999; 99 Tadros T, Klein M, Shapira O. Circulation 2009; 119 Tzemos N, Lyseggen E, Silversides C, JACC 2010; 55

44 Outcome in Adults with BAV Michelena H, Desjardins VA, Avierinos JF, et al. Circulation 2008; 117 Tzemos N, Therrien J, Yip J et al. JAMA 2008; 300

45 Overall Survival in BAV 212 adults without signif. aortic valve dysfunction at baseline: Survival similar to matched controls (Olmstedt County) 27% OP within 20 y, mean age 40 ±20 y. Valve degeneration strong predictor: thickening, calcification, mobility Michelena H, Desjardins VA, Avierinos JF et al. Circulation 2008; 117

46 Outcome in BAV: Aortic Complications. Community-based, long-term FU 416 pts BAV, age 35±21 (79% >18y), 69% male, FU up to 25y, Olmstedt Cty Survival overall similar to general population confirmed AVR probability 52 % at 25y, 61% due to AS, 30% AR Predictors : Age p=0.01 AV Vel >2, p< Survival n.s. between AVR and non-avr pts AVR restores survival to general population AVR risk 50% at 25 years Michelena H, Sundt T, Desjardins V, Suri R, Pellikka P, Enriquez-Sarano M. ESC 2010

47 Risk of Aortic Aneurysm and Dissection in BAV Predictors of aortic events including OP: Age >50, baseline aortic diameter >40mm. Influence of hypertension, more males. 1% risk aortic dissection 40% had aneurysm at 25y Aortic surgery probability 26 % at 25 y Events 20 % 10 0 AA AD 40 ± 5% 1 ± 0.5% Time years Michelena H, Sundt T, Desjardins V, Suri R, Pellikka P, Enriquez-Sarano M. ESC 2010

48 BAV: Contemporary Outcome >50% pts surgery as adults, survival comparable Aortic dissection 1% at 25y Aneurysm risk 40% at 25y Aortic surgery probability 26 % at 25 y Regular imaging of aortic root, ascendens No association BAV phenotype with aortic complic. Endocarditis 5% at 25y, high morbidity (AVR, death) Michelena H, Sundt T, Desjardins V, Suri R, Pellikka P, Enriquez-Sarano M ESC 2010

49 Conclusion Outcome of AS determined by interplay of valvular obstruction and hemodynamic consequences. BNP, LV strain easy to assess for monitoring AS, in addition to AV-Velocity and calcification. LVH (mass) and LA size reflect further risk. Contemporary survival in BAV favorable, although >50% surgery as adults. Regular imaging of aorta. Identify future preventive treatments of progression of AS (metabolic, atherosclerotic, hypertensive )

50 Thank you

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52 What determines the outcome in AS? Severity of obstruction - AV-Velocity, gradients, valve area - Calcification amount Pathophysiological consequences - LVH, LV mass - Diastolic dysfunction, LA dilatation - Systolic LV function: EF, TDI, strain, contractile reserve - BNP release Other factors - Age, gender - Comorbidities (renal failure, diabetes, pulmon, CAD ) - Metabolic, atherosclerotic factors, inflammation - Postop.: prosthesis related factors, mismatch, EF Interplay of determinants

53 2D Strain and BNP reflect Afterload and Early Myocardial dysfunction Highest BNP and low systol. strain in increased afterload N=173 asympt. severe AS, EF 55, 22% Low SVi <35 ml/m² Valvulo-art.impedance Zva= Syst. BP + mean transvalv gradient / Svi Zva < 5 mmhg ml/m² Zva > 5 Lancellotti P, Donal E, Magne J, Eur J Echo 2010 March

54 Metabolic Syndrome and Outcome in AS? Retrospective, N=105 asympt. AS, AVA<1.5, Metabol. Syndr 38% More events and AVR with MetS, faster AVA progression (independent of statin use) Event free survival and MetS Briand M, Lemieux I, Dumesnil JG, Pibarot P et al. JACC 2006; 47

55 Am J Cardiol 2010; 105: More eccentric hypertrophy in obese AS pts, independent of hypertension and severity of AS, although higher prevalence of hypertension in obese, LV hypertrophy does not only reflect AS severity