1. Department of Surgery, University of Pennsylvania Health System Which Operation is Best for Severe Ischemic MR: Repair or Replace? Michael Acker William Measey Professor of Surgery Chief of Division of Cardiovascular Surgery Director of Heart and Vascular Center University of Pennsylvania Health System

2. AHA/ACC and ESC Guidelines No conclusive evidence for superiority of repair or replacement Class I Level C evidence for IMR patients undergoing CAB w/ EF > 30% Class IIa Level C evidence for IMR patients undergoing CAB w/ EF < 30% Class IIb Level C evidence for IMR patients not undergoing CAB Class IIb Level C evidence for severe secondary MR

3. Treatment Choice is Controversial Lower periop morbidity and mortality with repair – Vasileva et al, Eur J Cardiothoracic Surg 2011;39:295-303 Better long-term correction with replacement – Di Salvo et al, J Am Coll Cardiol. 2010; 55:271-82 – Grossi et al, J Thorac Cardiovasc Surg 2001;122:1107-24 – Gillinov et al, J Thorac Cardiovasc Surg 2001;122:1125-41 Based on retrospective observational studies Need randomized evidence

4. 4 Functional MR secondary to dilated cardiomyopathy: Bolling Hypothesis: “an annular solution for a ventricular problem”-- such that reconstruction of the MV annulus’ geometric abnormality by an undersized ring restores valvular competency, alleviates the excessive ventricular workload, improves ventricular geometry and improves ventricular function.

5. Department of Surgery, University of Pennsylvania Health System Mitral Annuloplasty Rings Reduce posterior annular circumference Push posterior leaflet forward for better coaptation ie decrease septal lateral dimension

6. Department of Surgery, University of Pennsylvania Health System MV Repair Techniques for Functional MR (Ischemic or Non-ischemic) Undersized Annuloplasty Ring- standard of care; most common of repair techniques ?Techniques to specifically address leaflet tethering— Promising but not fully tested: cutting secondary chords papillary muscle relocation

7. Department of Surgery, University of Pennsylvania Health System Downsized, rigid rings showed positive results at 4-year follow-up Methods: 85 consecutive patients with previous infarction, LV dysfunction (EF 30%) and severe MR underwent CABG and restrictive mitral annuloplasty with stringent downsizing (2 rigid complete ring sizes). Pre-op Pre-op 4 years p-value NYHA class 2.91.2<0.0001 LVEDD (mm) 59.854.2<0.0001 LVESD (mm) 46.339.3<0.0001 LA dimension (mm) 4542<0.01 MR grade 3.00.8<0.0001 LVEDD = left ventricle end-diastole dimension; LVESD = left ventricle end- systolic dimension; LA = left atrium Bax et al. Restrictive annuloplasty and coronary revascularization in IMR results in reverse left ventricular remodeling. Circ 110:II 103-II108 2004 Braun et al: Preoperative left ventricular dimensions predict reverse remodeling following restrictive mitral annuloplasty in IMR. Eur J CT Surg 27(5):847-853 8% mortality No recurrence of > 2 MR at 18 mo No reverse remodeling seen with LVEDD>65mm Cannot Discount effect of Revascularization On Hybernating Myocardium leading to Reverse Remodeling

8. Tethering Mechanism for recurrent MR after repair

9. Severe IMR Randomized Comparison of MV Repair vs Replacement Moderate/severe MR by TTE assessment in surviving pts at 30 days, 6, 12 and 24 months

10. Severe IMR Randomized Comparison of MV Repair vs Replacement Cumulative incidence of MR recurrence and/or death over 2 years (n=116)

11. 11 Preservation of entire MV apparatus has been demonstrated to preserve ventricular geometry, decrease wall stress, improve systolic and diastolic function Must maintain chordal, annular and subvalvular continuity Is the Best Repair a Replacement? Comparisons of results to Era where subchordal apparatus was excised not valid

12. (Enriquez-Sarano et al. Circulation 2003;108:253-256) MV Repair vs Replacement MayMay Mayo Clinic: ICM -- no difference in survival between replacement and repair

13. 13 Mitral valve repair or replacement for ischemic mitral regurgitation? The Italian Study on the Treatment of Ischemic Mitral Regurgitation (ISTIMIR) Lorusso R et al. J Thorac Cardiovasc Surg 2013; 145:129-39 Propensity matched

14. 14 Mitral valve repair or replacement for ischemic mitral regurgitation? The Italian Study on the Treatment of Ischemic Mitral Regurgitation (ISTIMIR) Lorusso R et al. J Thorac Cardiovasc Surg 2013; 145:129-39

16. Primary Endpoint Degree of left ventricular reverse remodeling −Assessed by left ventricular end systolic volume index (LVESVI) using TTE at 12 months −Group difference based on Wilcoxon Rank-Sum test with deaths categorized as lowest LVESVI rank Powered (90%) to detect an improvement of 15mL/m 2 from repair to replacement in LVESVI at 12 months

17. Median change in LVESVI Change in LVESVI (mm/m 2 ) Repair Replacement Repair Replacement (All pts) (All pts) (Survivors) (Survivors) Median with 95% CI for change in LVESVI from baseline to 1 yr Z=1.33, p=0.18 (All pts)

18. Recurrent MR at 1 year

19. LVESVI with Recurrent MR p < 0.001

20. Primary end point LVESVI (ml/m2)MR ≥2+ (%) RIME Trial CABG67.4 (-6%)50 CABG + MV repair56.2 (-28%)4 P-value0.002<0.001 CTSN Mod MR Trial CABG46.1 (-17%)30 CABG + MV repair49.6 (-16%)11 P-valueNS<0.001 CTSN Severe MR Trial CABG + MV repair (overall)54.6 (-11%)33 CABG + MV repair (recurrent MR)64.1 (+5%)100 CABG + MV repair (no recurrent MR)47.3 (-22%)0 CABG + MV replacement60.7 (-10%)2 Comparison with other randomised controlled trials

21. Mortality 30 Day Mortality: 1.6% (repair) vs. 4.0% (replacement), p =0.26 12 Month Mortality: 14.2% (repair) vs. 17.6% (replacement), p =0.47

22. MACCE at 12 Months

23. Serious Adverse Events P=NS

24. Quality of Life at 1 year Δ=16.6% Δ=18.4%Δ=46.9% Δ=19.6%

25. NYHA Classification & Death

26. Restrictive mitral valve annuloplasty versus mitral valve replacement for functional ischemic mitral regurgitation: Am exercise echocardiographic study. Fino et al. J Thorac Cardiovasc Surg 2014;148:447-53 26 Physio-17% 28 Physio-51% 30 Physio-29% 32 Physio-3% 27 CE-23% 29 CE-26% 31 CE-3% 27 SJ-8% 29 SJ-26% 25 SJ-3% 27 Carbomedics-8% 29 Carbomedics-3% MV Repair-35 MVR - 35

27. Restrictive mitral valve annuloplasty versus mitral valve replacement for functional ischemic mitral regurgitation: Am exercise echocardiographic study. Fino et al. J Thorac Cardiovasc Surg 2014;148:447-53

28. Determinants of long term functional capacity in patients undergoing mitral valve annuloplasty or mitral valve replacement for ischemic mitral regurgitation. Fino et al. AHA Nov 2014

29. 10 Variable Model of MR Recurrence and/or Death Age BMI Gender Race EROA Basal Aneurysm NYHA History of CABG History of PCI History of Ventricular Arrhythmia

30. ROC Curve: 10 Variable model of Recurrence/Death

31. Basal Aneurysm

32. Preoperative 3D Valve AnalysisPredicts Recurrent IMR after Mitral Annuloplasty—Gorman lab 50 pts with Severe IMR undergoing MV repair with small annuloplasty ring comparing recurrence of mod to severe MR to those without recurrence

33. Conclusions -2D echocardiographic studies identified different predictors of IMR recurrence, but results are inconsistent and generally inadequate to predict IMR recurrence -3D echocardiography combined with valve modeling is predictive of recurrent IMR -Preoperative regional leaflet tethering of P3 is a strong independent predictor of IMR recurrence after undersized ring annuloplasty -In patients with IMR and a preoperative P3 tethering angle ≥29.9° chordal- sparing mitral valve replacement rather than mitral valve repair should be strongly considered

34. Repair vs Replacement for Severe Ischemic MR Does it result in improved survival? – Early/late?--NO Does it result in decreased complications? – NO (at one year) Does it result in more LV reverse remodeling? – NO (at one year) Does it result in improved freedom from hospitalizations or symptoms of heart failure? – NO (at one year) Is Replacement a more reliable operation for longterm freedom from recurrent MR? -YES (longterm benefits will be seen because of absence of MR ?) -Can we predict recurrence? -Predictive models of recurrence of IMR are being developed to allow for customization of repair vs replacement for individual pt with severe IMR

35. Conclusions Recurrent MR at least to a moderate degree occurs early (6mo) and is a common event at 2 years after MV repair with an undersized annuloplasty ring— clinical impact yet unkown? MVR provides a more durable correction of severe IMR with no differences seen in reversal of LV remodeling or clinical outcomes – MR recurrence may have an important effect on long-term outcomes MVR with complete chordal sparing is a safe and acceptable option in pts with severe IMR-supported by LEVEL of EVIDENCE “A”

36. So What Do I Do? I continue to repair about 70% of IMR with small complete annuloplasy ring while replacing about 30% – Degree of tethering; age of pt; need for anticoagulation; – Await 2 and 5 year data on effect of recurrent moderate MR on clinical outcome 2 year follow-up to be presented AHA Nov 2015