Natural History of Mitral Regurgitation · Natural History of Mitral Regurgitation (degenerative and ischemic) Indications for Surgery Monterey Bay Regional Heart Symposium 30 April

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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


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%


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


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


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)


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Overall Survival - Patients With Asx Organic MR - Medical RxDeath From Cardiac Causes


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


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


Cardiovascular Morbidity - Baseline Risk Factors


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MVP-related Events - Baseline Risk Factors


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


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

are needed to see this picture.

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


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


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


Sur

v iva

l -F

ree

o f L

VD

SD



Incremental Value - When BNP Added to Echo Variables


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


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


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

Documents

Natural History of Mitral Regurgitation · Natural History of Mitral Regurgitation (degenerative and ischemic) Indications for Surgery Monterey Bay Regional Heart Symposium 30 April