©2015 MFMER |

The Pathophysiology and

Management of Functional Mitral

Regurgitation

What are the questions?

Banff 17

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©2015 MFMER |

Primary

• Pathological abnormalities of the mitral apparatus

Secondary (“Functional”)

• Normal or nearly normal mitral leaflets are prevented from proper coaptation by underlying LV dysfunctionproducing tethering, mitral annular dilation, or both

Differences between Primary vs Secondary M. Regurgitation

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Mitral Annulus

Papillary muscle

LA

AO

Chordae

Normal Mitral Valve

LV

Functional Mitral Regurgitation

Papillary muscle

displacement

MR

AO

Tethered Chordae

LVIschemic LV

Distortion

Restricted Leaflet Closure

Annular dilation

©2015 MFMER |

Clinical Significance of Mild MR after MI

• 727 pts

• SAVE trial

• MI 16 days

• LVEF 40%

Ca

rdio

va

scu

lar

su

rviv

al

Lamas: Circ, 1997

Days

Cumulative CV Survival

0.5

0.6

0.7

0.8

0.9

1.0

0 200 400 600 800 1000 1200 1400

MR present

MR absent

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M. Regurg. on Angiography

141 pt 19.4%

Severity

1+ – 14.6%2+ – 4.5%3+ – 2 pts

71%

53%

©2016 MFMER |

• 303 patients• Prior (>16 days) QMI• Mayo Clinic

Ischemic MR: Outcomes Stratified by the Degree of MR

0

20

40

60

80

100

0 1 2 3 4 5

Grigioni Circ, 2001

0

20

40

60

80

100

0 1 2 3 4 5

Surv

ival (%

)

Survival Stratified by R. Vol Survival Stratified by ERO

*P=0.002 on multivariate analysis **P>0.004 on multivariate analysis

RVol01-2930

ERO01-1920

Years Years

* **

61±6

44±9

35±7

61±6

47±8

29±9

P<0.0001P<0.0001

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Prognostic Impact of Functional MR

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Both

Presence of MR Severity of MR

Surrogate? Causality?

©2017 MFMER |

Management of Functional MR

issues

In pts with moderate MR• CABG alone vs CABG + mitral annuloplasty/repair

In pts requiring a mitral valve procedure (moderate to severe MR)

Mitral valve repair

Mitral valve replacement

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Therapeutic Considerations for Ischemic MR in Patients With LV Dysfunction

Guideline based medical therapy to address LV

dysfunction

Coronary revascularizationalone

• Pharmacologic

• CRT

Beta blockers*

ACE/ARB*

Diuretics*

Isordil*

Aldosterone antagonists**Improvements documented

Indications

Extensive ischemia

Angina

Viability

Inconsistent effect

on severity of MRMV Replacement/Repair

Surgery & Devices

LVAD/Cardiac transplantation

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The results of mitral valve repair for functionalmitral regurgitation are much inferior to those

in patients with degenerative MR

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Durability of Ischemic Mitral Valve Repair

• 78 patients

• Ischemic MR

• Mean follow-up 28 mo

MR

gra

de 3

+ o

r 4+

(%

)

Jerri: JTCVS, 2006Mihaljevic et al: JACC 49:2191, 2007

Time after operation (in log scale)

Recurrence of Severe MR AfterCABG ± Annuloplasty in Ischemic MR

0

10

20

30

40

50

60

70

0 1 week 7 weeks 1 year 7.4 years

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Recurrent MR (2+) – 32%

Severe MR (3-4+) – 20%

• Recurrent severe MR lower with annuloplasty, but still 20% at 5 years

CABG alone (290 pts)

CABG + MV annuloplasty

(100 pts)

©2016 MFMER |

Effect of Mitral Valve Annuloplasty in Patients With LVEF ≤30%

• 419 patients

• Retrospective analysis

• Consecutive series

Event0

free s

urv

ival

Clinical Trials.gov NCT 00608140

Days

Survived Free of Death/VAD/Cardiac Transplant

0.00

0.20

0.40

0.60

0.80

1.00

0 500 1,000 1,500 2,000 2,500

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Effectiveness of Surgical Mitral Valve Repair Versus Medical Treatment for People With Significant Mitral Regurgitation and Non-Ischemic Congestive Heart Failure (SMMART-HF)

This study has been terminated (unable to recruit sufficient numbers of patients

P=NS

No MVA

(surgical candidate)

MVA

Wu: JACC, 2005

©2016 MFMER |

Randomized Trials of Surgical Treatmentin Moderate Ischemic Functional MR

JTCVS, 2009; Circ, 2012; NEJM, 2014

Follow-up OutcomesTrial Pt (no.) (years) (CABG + MVR vs CABG alone)

Fattouche e ↑ EF↓ VolumesImproved NYHA class

102

Chan(RIME Trial)

73

Smith(CTS Network)

301

5

1

2

↓ LV reverse remodeling↑ Peak O2 consumption↓ M regurgitation↓ BNP

No change in LVESVModerate → severe MRBypass time and hospital stayPerioperative neurologic events

No trial powered for major clinical outcomes

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©2015 MFMER |

?Impact onlong-term

clinical outcomes

Mitral Annuloplasty vsReplacement for Functional MR

Periop. mortality and morbidity in some centers

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Higher risk of persistent MR

Replacement

Repair

©2015 MFMER |

Mitral Valve Repair vs Replacement for Severe Ischemic MR

CTSN Trial – 2-Year Outcomes (251 Patients)

6.5

9.0

0

5

10

15

20

25

30

35

Goldstein: NEJM, 2015

mL

/m2

Replacement

Repair

3485852-6

Decrease in LVESVfrom Baseline Mortality

Moderate Severe MR Recurrence

23.2

19.1

1.3

31.3P=0.39 P<0.001P=0.19

Repair patients - higher rate of serious heart failure, 24% vs 15% (P=0.05) and more CV readmissions 48.3 vs 32.2 (P=0.01)

©2015 MFMER |

• No concrete evidence that surgery alters natural history

• High risk of recurrence after MV Repair

• Significant morbidity and mortality with MV replacement in some series

Should Moderate to Severe Functional MR be Corrected?

Caveats

Intuitively– Yes

Ongoing trials are important for both approaches

Surgery vs

Medical

Percutaneous vs

Medical

Percutaneousvs

Surgery

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AnnuloplastyvsOther techniques

©2016 MFMER |

LVEF 0.04

LVEF <60% 44.1 41.2 0.83

LVEF ≥60% 44.1 74.4 0.001

Subgroup

Percutaneous

Repair, % Surgery, % P value Difference [95% CI]

Interaction

P value

Sex 0.89

Male 42.9 63.9 0.03

Female 46.4 65.0 0.15

Age 0.005

Age ≥70 yrs 45.1 42.3 0.81

Age <70 yrs 43.4 83.3 <0.001

Randomized Trial Data of Mitra-Clip vs Surgery in Functional vs Degenerative MR

Feldman: JACC, 2015

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EVEREST II TrialSubgroup Analyses for Freedom From Death, MV Surgery or Reoperation, and 3+ or 4+ MR at 5 Years

Surgery better Percutaneous repair better

Type of MR 0.02

Functional MR 40.5 28.6 0.43

Degenerative MR 45.5 76.2 <0.001

-60 -40 -20 0 20 40 60

©2016 MFMER |

ESC/EACTS Guidelines for Mitra-Clip

COAPT RESHAPE MITRA-FR

Del Trigo: Circ CV Intv, 2015

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Class IIB LOE-C

Approved for Both Primary and Secondary MR

Design/location

Multicentre and

randomized;

US

Multicentre and

randomized; EU

Multicentre and

randomized; France

No of patients 430 800 288

LVEF, % ≥20%–≤50% ≥15%–≤40% ≥15%–≤40%

MitraClip System for the Treatment of FMR:

Ongoing Randomized Trials vs Medical Therapy

©2015 MFMER |

Functional Mitral Regurgitation –Conclusions

• FMR predicts increased mortality in a graded fashion

• CABG alone can reduce FMR acutely in some patients – results unpredictable

• Medical therapy including beta-blockers, ACE-1 ARB is effective

• FMR is common in CHF and after MI

• FMR is primarily a disorder of the LV

• CRT may be effective in some patients

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Functional (Secondary) MR‟Evidence and Uncertainties”

• Does correcting FMR prolong or improve the quality of life?

• Trials with Mitraclip / Devices will help inform the field

• If correcting FMR is demonstrated to help:then providing the most complete and durable correction is desirable

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May depend upon presence of CHF symptoms

Predictors of recurrences after repair

• Severe tethering

• Inferobasal aneurysm

• Severe LV dilatation

Valve-sparing mitralvalve replacementshould be usedmore liberally inthese patients

©2015 MFMER |

When to Intervene on the Mitral Valve in a Patient Undergoing CABG

Mild moderate MR

Dominant Symptom –Angina

Severe MR

Dominant symptom –CHF

CABG alone

or

CABG plus

mitral annuloplasty

Valve sparingMV replacement

vsRepair

Trials suggest replacement is preferred

over repair

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Annuloplasty Other techniques

©2015 MFMER | 3459251-9

Evolving Concepts in regard to the

Management of Functional MR

We now understand much more

about what we do not know

©2016 MFMER | 3623525-2

Kron: JTCVS, 2017

Existing Association Guidelines AATS Guidelines

Moderate Ischemic MR

A. MV repair may be considered at time of other

cardiac surgery, including CABG

(COR IIb, LOE B)

Moderate Ischemic MR

A. MV replacement is reasonable in patients with

severe IMR who remain symptomatic despite

guideline directed medial and cardiac device

therapy, and who have a basal aneurysm/

dyskinesis, significant leaflet tethering, and/or

severe LV dilation (EDD >6.5 cm)

(COR IIa, LOE B)

Mitral Valve Replacement (MVR) vs

Repair

Not available

Mitral Valve Replacement (MVR) vs

Repair

A. MVR for IMR is performed with complete

preservation of both anterior and posterior leaflet

chords (COR I,LOE B)B. MV repair for IMR is performed with small

undersized complete rigid annuloplasty ring

(COR IIa, LOE B)

©2016 MFMER |

Updated AATS Guidelines

Kron: JTCVS, 2017

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Severe Ischemic MR Severe Ischemic MR

A. MV surgery is reasonable at time of

other cardiac surgery (eg, CABG, AVR)

(COR IIa, LOE C)

B. MV surgery may be considered as an

isolated procedure for treatment of

patients with severe symptoms (NYHA

III/IV) despite GDMT (COR II, LOE C)

A. MV replacement is reasonable in

patients with severe IMR who remain

symptomatic despite guideline directed

medial and cardiac device therapy, and

who have a basal aneurysm/dyskinesis,

significant leaflet tethering, and/or severe

LV dilation (EDD >6.5 cm) (COR IIa, LOE

B)B. MV repair with an undersized complete

rigid annuloplasty ring may be considered

in patient with severe IMR who remain

symptomatic despite guideline directed

medical and cardiac device therapy and

who do not have a basal

aneurysm/dyskinesis, significant leaflet

tethering, or severe LV enlargement

(COR IIb, LOE B)

Existing Association Guidelines AATS Guidelines

©2016 MFMER |

Why is the Benefit of MR Reduction so Hard to Prove?

• MR recurrence 20%; perioperative mortality 1.5-15%

3507143-03

• The benefit may be limited to specific pt subgroups that have not been pre-defined in CV datasets

M. Mack (Pers. Comm), 2016

• Perhaps there is no benefit ? – MR is a surrogate not causally related to outcome ?

• “Things may not be as they seem”

Gersh And Frye NEJM 2008

EtiologyDurationof MR

LVEFMR severity

F. ClassAnatomy of

MV apparatus