natural history of mitral regurgitation · natural history of mitral regurgitation (degenerative...
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Natural History of Mitral Regurgitation(degenerative and ischemic)
Indications for Surgery
Monterey Bay Regional Heart Symposium30 April - 1 May 2010
Melvin D. Cheitlin, MD, MACCEmeritus Professor of Medicine
University of California San Francisco
Natural History of Chronic MR
Purpose - choose optimum time for surgery
Absent hypertension, no indication for medical therapy
Natural history depends on etiology
LeafletsRHDMVPIE
ChordaeRuptureTrauma
Papillary muscleCADTrauma
LV wallCADCardiomyopathy
Connective tissue disCongenital clefts
AnnulusCalcificationDilated LV
Temporal Changes in the Etiology of Pure MR
694 excised valves
Edwards WD. In Harrison’s Advances in Cardiology, Braunwald ed. 2003, p 317
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Mitral Regurgitation - Pathophysiology
Chronic MR is a preload burden on the LV
LVEDV increases - eccentric LVH
↑ LV stroke volume = Effective SV + Regurg SV
↑ LA pressure ➙ ↑ left atrium
Pulmonary hypertension - late in the course
End systolic pressure volume relationship
ESPVR
LV P
ress
u re
(mm
Hg)
LV Volume
ED volume
LV stroke volume
↓
↓LV EF
ESP falls along ESPVR
Normal
MR, normal contractility
MR, reduced contractility
ESPV
↓contractility
volume
Pre
ssu
re
→ EDV↑ ESV↓LVEF
↑ EDV→ ESV↑ LVEF
→ EDV↑ ESV↓ LVEF
Mitral Regurgitation - Effect of Change in Contractility
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Overall Survival - Mitral Valve Repair vs Replacement For Severe MR
Enriquez - Sarano M, et al. Circulation 1995;91:1022
Clinical Outcome of Mitral Regurgitation Due to Flail Leaflet
229 patients with isolated MR due to flail leaflets - Dx 1980-’89NYHA class I-II 162 (71%) Class III-IV 66 (28%)
Ling L et al. N Engl J Med 1996;335:1417-1423
86 patients treated medically Survival by NYHA class -Rx medically
MortalityNYHA I-II 4.1%/yrNYHA III-IV 34.0%/yr
Mortality 6.3%/yr
Independent determinants of mortalityOlder age, NYHA class, and lower EF
Ling L et al. N Engl J Med 1996;335:1417-1423
Long-Term Survival with Medical Treatment,According to the Ejection Fraction (EF)
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Natural History of Medically Rx Patients With MR Due to Flail Leaflets
Ling L, et al. N Engl J Med 1996;335:1417
Surgery in Patients With MR Due to Flail Leaflets
Surgery performed in 143 patients 23±32 months after diagnosis
MV repair in 95 patients. MVR in 47 patients
Indications for surgery:
NYHA Class III-IV dyspnea 107 (75%) Physician’s preference 24 (17%) Infective endocarditis 5 ( 4%) Angina pectoris 4 ( 3%) Thromboembolism 1 (0.7%) Undetermined 2 (1.4%)
Concomitant CABG 29 patients
Perioperative mortality 4%
Ling L et al. N Engl J Med 1996;335:1417-1423
Flail Leaflet Mitral Regurgitation-Long-Term outcome
Ling LH. Circulation 1997; 96:1819
221 patients (1980-1989) Age 65 +/- 13 years
Gr I Surg </= 1 month63 patients(Op Mort- 1.6%)
Gr II Med Rx158 patients
(80 later surg - Op Mort- 6.3%))
AgeNYHA III-IVAt Fib at StartComorbid indexEF
61.1 +/- 1440 (63%)20 (32%)0.4 +/- .7965% +/- 9%
66.5 +/- 1220 (13%)28 (18%)0.73 +/- 165% +/- 9%
P value.009<.0001.02.01ns
Baseline
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Flail Leaflet Mitral Regurgitation-Over-all Outcome
Ling LH. Circulation 1997; 96:1819
Survival 10 yearsCHF at 10 years
79+/- 8%27 +/- 7%
65 /- 5%60 +/- 7%
Gr I Gr II
Multivariate predictors for Survival
AgeEFNYHA ClassEarly Surg
1.1 (1.06-1.13)0.95 (0.93-0.98)1.65 (1.21-2.25)0.31 (0.13-0.72)
Risk Ratio (95% CI)
Same order for CV death, CHF, new-onset at fib
p value0.00010.00020.0020.006
Ling, L. H. et al. Circulation 1997;96:1819-1825
Overall Survival From Time of Diagnosis - Patients With Flail Leaflets -Early Surgery vs Conservative Management
Ling, L. H. et al. Circulation 1997;96:1819-1825
Survival adjusted to age and ejection fraction according to the management strategy selected at baseline for patients in New York Heart Association class I or II (left) and for
those in class III or IV (right)
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Cardiac Death - MR With Flail Leaflets -Management Selected at Baseline
Ling, L. H. et al. Circulation 1997;96:1819-1825
Overall Survival - Patients With Asx MR - Medical Rx - ERO
Enrique-Sarano M, et al.New Engl J Med 2005;352:875
N=456 ptsAge 63 ±14 yrsLVEF 70±8%
Cardiac Events - Asx MR Stratified by ERO
Cardiac Events(Death, CHF, Atrial Fib)
Enrique-Sarano M, et al.New Engl J Med 2005;352:875
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Overall Survival - Patients With Asx Organic MR - Medical RxDeath From Cardiac Causes
Enrique-Sarano M, et al.New Engl J Med 2005;352:875
N=456 ptsAge 63±14 yrsLVEF 70±8%
Late Survival after MV Repair or Replacementat Reoperation for Recurrent MR
Suri RM, et al. J Thorac Cardiovasc Surg 2006; 132:1390
Mortality and Morbidity - MVP First Diagnosed Between 1989 and 1998Natural History of Asx MVP in the Community
Avierinos JF, et al. Circulation 2002;106:1355
Cardiac morbidityCHFEndocarditisMV surgery
n = 833 pts4581 pt-yrs F-U
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Baseline Risk Stratification Used in 833 Olmsted County, Minn, ResidentsFirst Diagnosed With MVP Between 1989 and 1998
Primary RFs (Excess Mortality) Secondary RFs (CV Morbidity)
EF <50% Slight MRMR moderate Flail leaflet
LA diameter >40 mmAFAge >50 y
Avierinos JF, et al. Circulation 2002;106:1355
MVP - Survival According to Categories of Baseline Risk Factors
P(exp) = probabilities - difference between observed and expected mortalityP(dif) - differeence in total mortality between subgroups
Avierinos JF, et al. Circulation 2002;106:1355
Cardiovascular Morbidity - Baseline Risk Factors
Avierinos JF, et al. Circulation 2002;106:1355
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MVP-related Events - Baseline Risk Factors
Avierinos JF, et al. Circulation 2002;106:1355
MVP-related eventsDeathCHFEndocarditisMV surgery
447 consecutive Asx patients with MVP or flail leafletsSevere MR and preserved EF (>60%)
2 Groups: Conventional management - 286Early surgery - 161
Follow-up - median 5.4 years
Operative Groupno operative mortalityno cardiac deaths2 repeat surgeries
Conventional Rx Group12 cardiac deaths1 repeat surgery22 admissions for CHF
127 propensity score-matched pairs -
Cox multivariate analysis in the Conventional Rx group:Independent variables predicting late CHF or indications for surgery:
Baseline grade of pulmonary hypertension (HR 1.9)Age (HR 1.02)ERO (HR 2.1)
Conventional Rx vs Early Surgery - Severe MR
Kang DH, et al. Circulation 2009;119:797
Conventionally managedGroupn = 286
Did not developSurgical criterian = 207 (72.4%)
3 sudden cardiacDeaths
2 deaths - IE
DevelopedSurgical criterian = 79 (27.6%)
Symptomaticn = 66
Asymptomaticn = 13
Surgeryn = 53
n= 50 n= 3
5 CHF deaths1 sudden death
1 CHF death
Kang DH, et al. Circulation 2009;119:797
Cardiac Death - Conventional Rx Group of MR PatientsMVP or Flail leafletsSevere MRMedian F-U 5.4 yearsLVEF >60%
Conventional RxSurgical indications:
Exertional dyspneaLVEF < 60%ESD > 45 mmPASP > 50 mm Hg
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QuickTime™ and a decompressor
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Comparison of event-free survival rates between the operated (OP)and conventional treatment (CONV) groups in propensity-matched pairs.
Events = operative death, cardiac death, repeat MV surgery, CHF hospitalization
Kang DH, et al. Circulation 2009;119:797
Prognostic Usefulness of BNP in Severe Asx MR - LVEF > 60%
269 consecutive patientsFirst 167 - Derivation Group - mean F-U 36±8 mo.Second 102 - Validation Group - mean F-U 31±9 mo
Combined endpoint:CHF symptoms, LV dysfunction, death (LVDSD) on follow-up
ROC characteristics - optimal cut-off value 105 pg/ml BNPdiscriminated high risk patients in both cohorts:
Derivation Gr - 76% vs 5.4%Validation Gr - 66% vs 4.0%
BNP was strongest independent predictor
Pizzaro R, et al JACC 2009;54:1099
0
10
20
30
40
50
60
70
80
< ≥ < ≥105 pg/ml 105 pg/ml
Derivation Set Validation Set
LV
DS
D (
%)
5.4
76
4.0
66
p = 0.001
p = 0.001
Pizzaro R, et al JACC 2009;54:1099
Severe MR - BNP Levels Predict Combined Endpoint
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Sur
v iva
l -F
ree
o f L
VD
SD
Derivation Set Validation Set
Survival Free of LVDSD According to BNP Levels
Pizzaro R, et al JACC 2009;54:1099
Sur
v iva
l -F
ree
o f L
VD
SD
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Incremental Value - When BNP Added to Echo Variables
Pizzaro R, et al JACC 2009;54:1099
Area = 0.80 Area = 0.91
Area = 0.79 Area = 0.89
Months
0 25 50 75
% a
syp
tom
atic
pa
tien
tsW
ith n
orm
al L
V f
un
ctio
n
0
0.25
0.50
0.75
1.00
54 ± 6%
Kaplan-Meier analysis according to clinical course in 128 patients
5 years
Krauss J, et al Am Heart J 2006;152:1004
Asymptomatic severe organic MR - LVEF 66 ± 3%
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Symptom or LV Systolic Dysfunction (SLVSD) - Free Survival
Krauss J, et al Am Heart J 2006;152:1004
Asymptomatic Severe Mitral RegurgitationIs Watchful Waiting Good Enough?
132 asymptomatic consecutive patients -severe MR due to MVP or flail leafletAge 55 ±15 years
Referred to surgery:SymptomsLV enlargement (LVESD 45 mm or ESDI 26 mm/m2)LV dysfunction (LVEF <.60 or Fractional shortening < 0.32)Pulmonary hypertension (Systolic pressure > 50 mm Hg)Recurrent atrial fibrillation
Followed up 62 ± 26 months.Reevaluated at 3, 6, 12 months, then yearly
38 (29%) patients developed criteria for surgery,Symptoms 24 (63%) LV criteria 9 (24%)Pulm hyper or atrial fib 5 (13%)
Rosenhek R, et al Circulation 2006;113 : 2238.
Event-Free Survival
Rosenhek R, et al Circulation 2006;113 : 2238.
34 had surgery4 refused surgery
92%At 2 y
78%At 4 y
65%At 6y
55 %At 8y
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Survival of Asx Patients with Severe Degenerative MR Followed Medically
Rosenhek R, et al Circulation 2006;113 : 2238.
Mitral Regurgitation - Indications For SurgeryClass I
1. Symptomatic patient with acute severe MR (B)2. Chronic severe MR - NYHA II-IV, with EF > 0.30 and/or ESD >55 mm (B)3. Asx chronic severe MR, EF 0.30-0.60 and/or ESD > 40 mm (B)4. MV repair preferred over MVR when surgery needed. [C]
Class IIa1. Asx patients with chronic severe MR with EF >0.60 and ESD
< 40 mm where successful repair is > 90% (B)2. Asx patients with chronic severe MR, EF >0.60, and
new-onset atrial fibrillation [C]3. Asx patients with chronic severe MR, EF>0.60 and PASP > 50 mm Hg
at rest or > 60 mm Hg with exercise [C]4. Chronic severe MR due to primary valve disease, NYHA III-IV,
and EF < 0.30 and/or ESD > 55 mm where repair is likely [C]Class IIb
Chronic severe secondary MR due to severe LV dysfunction(EF < 0.30), with NYHA III-IV despite Rx + bivent pacing [C]
Class III1. Asx patients with MR, EF>0.60 and ESD<40 mm, needing MVR [C]2. MV surgery not indicated for mild - moderate MR [C]
Bonow RO, et al Circulation 2008;118:e523-e661
Mechanism of Ischemic and PostInfarction MR
John Chan KM, et al Prog Cardiovasc Dis 2009;51:460
Global LVremodelingand dilatation
Normal mitralapparatus
Local LVremodelingand papillarymuscledisplacement
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Ischemic MR occurs in up to 40% of patients after AMIAronson d, et al. Arch Intern Med 2006;166:2362Lamas GA, et al. Circulation 1997;96:827
SAVE study - CV mortality:Mild IMR on medical Rx at 3.5 yrs - 29% No MR on medical Rx at 3.5 yrs - 12%
Presence of IMR independent predictor of CV mortalityOdds Ratio 2.0 (95% CI 1.23-3.04)
Severe heart failure:Mild IMR - 24%No IMR - 16%
P<0.001
P= 0.015
Lamas GA, et al. Circulation 1997;96:827
Severe heart failure:Mild IMR vs No IMR
Hazard Ratio 2.8(95% CI 1.8-4.2) P<0.001
Aronson D, et al. Arch Intern Med 2006;166:2362
Outcome worse as severity of IMR increases5-year survival
Mild IMR 47%Moderate - severe IMR 29%
Grigioni F, et al.Circulation 2001;103:1759
Ischemic MR Increases Future CV Events
Course of IMR After Isolated CABG is Variable
Moderate IMR at 6 weeks post CABGImproved (0 - trace) 8%Improved to mild 52%Persisted moderate 37%Developed severe 3%
Aklog L, et al Circulation 2001;104 (Suppl 1):1-68
Improved from moderate to none-mild 51%Remained moderate 25%Progressed to moderate to severe 12%Campwala SZ, et al. Eur J Cardio-Thorac Surg 2006;29:348
Six weeks post CABG22% of patients with moderate MR became severe
Lam B-K, et al. Ann Thorac Surg 2005;79:462
Predictors of Improvement of Unrepaired Moderate MRAfter Elective Isolated CABG
121 patients - Age 65±9 yrs
12 month follow-up57 no or mild MR (improved group)64 failed to improve
Predictors of Improvement before surgery
By Tech-99 and F18-FDG ≥ 5 segments of viable myocardium (OR 1.45)
Absence of dyssynchrony (<60 ms) (OR 1.49)
98% of patients with both had improvement
Only 34% with dyssynchrony and18% with non-viable myocardium
had improvement
32% with dyssynchrony and 49% with non-viable myocardiumhad worsening of MR
Penicka et al. Circulation 2009;120:1474
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Assynchrony between Papillary Muscles
improved
no improvement
Events:Death - any cause orHosp -worsening HF
Penicka et al. Circulation 2009;120:1474
Predictors of Improvement of Unrepaired Moderate MRAfter Elective Isolated CABG
Course of IMR After Isolated CABG is Variable
Cardiac function, Functional Class, and Survival all have varied after CABGcompared to those without IMR - depends on amount of revascularized ischemic vs nonviable myocardium and on ventricular geometry
Survival after CABG patients with IMRActuarial survival 88% - EF 36.2 ± 10% - 87% for isolated CABG
MV repair better than isolated CABG in ↓MR-op mo rtality higher with MV repair (12 % vs 2 % )
Kang DH. Circulation 2006;114:1499
Matched patients with and without IMR- no difference in survivalDuarte IG. Ann Thorac Surg 1999;68:426Mallidi HR. J Thorac Cardiovasc Surg 2004;127:636
Large studies with multivariate analysis2242 patients - CABG- mild-moderate IMR independent predictor
of ↓survival at 5 yearsOdds Ratio: Mild IMR 1.34 p=0.033, Moderate IMR 1.49 p=0.007
Grossi EA. Circulation 2006;114:15733264 patients - ↑IMR severity ↑risk of death after CABG
Hazard ratio 1.44 p<0.001Even mild IMR ↑risk HR 1.34 p<0.01
Schroder JN. Circulation 2005;112:(Suppl 1) I-293
Ischemic Mitral RegurgitationValve Repair vs Replacement
n = 482 pts with ischemic MR 1985 - ‘97
Valve Repair397
94%82%58%
Survival - multivariable, multiphase hazard function analysisPropensity-matched better-risk group
Valve Replacement85
30 day1 yr5 yr
High risk group - repair = replacement p = 0.4
Freedom from repair failure at 5 yrs = 91%
Risk factors - older age, higher FTC, greater WM abn, renal dysfunction
Gillinov AM, et al. J Thorac CV Surg 2001; 122:1125
81%
56% p = 0.08
36%
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MR Grade LVEF
Survival NYHA Class
Moderate Ischemic MR - CABG With and Without MV Repair
Goland S, et al. Texas Heart Inst J 2009; 36:416