1. UNIVERSITA' CAMPUS BIO-MEDICO DI ROMA Via Álvaro del Portillo, 21 - 00128 Roma - Italia www.unicampus.it Antonio Nenna, MD Department of Cardiovascular Surgery Università Campus Bio-Medico di Roma, Rome, Italy a.nenna@unicampus.it francesconappi2@gmail.com American College of Cardiology 2016, 65 th Annual Scientific Session ACC.16, April 2-4 2016, Chicago, USA Papillary Muscle Approximation versus Undersizing Restrictive Annuloplasty Alone for Severe Ischemic Mitral Regurgitation: a Randomized Clinical Trial Francesco Nappi, Cristiano Spadaccio, Antonio Nenna, Mario Lusini, Christophe Acar, Massimo Chello

2. ISCHEMIC MITRAL REGURGITATION Ischemic mitral regurgitation (IMR) is a consequence of myocardial ischemia which results in geometrical disturbance of mitral valve due to papillary muscle injury and displacement, favoring impaired leaflet coaptation. The incidence of IMR among patients with myocardial infarction is up to 39% (1,6 – 2,8 million patients in the US) Functional regurgitation  imbalance closing forces VS tethering forces Circulation 1997;96:827-33. Circulation 2001;103: 1759-64. Am J Cardiol 2002;89:315-8

3. ISCHEMIC MITRAL REGURGITATION Tethering forces: annular dilatation enlargement of the LV chamber abnormal displacement of the PM with apical and lateral migration J Am Coll Cardiol 2003;42:1929-32. Eur J Echocardiogr 2010;11:307-32. J Am Coll Cardiol 2014;63:2438-88 Closing forces: reduction of LV contractility global LV dyssynchrony PM dyssynchrony altered systolic annular contraction

4. TREATMENT Severe ischemic mitral regurgitation Coronary revascularization + mitral valve surgery Mitral valve replacement Mitral valve repair (undersizing restrictive annuloplasty) “MV repair is associated with better short-term and long-term survival compared to MV replacement” CTSN trial (NEJM, Acker, Goldstein): “MV replacement is associated to reduced recurrence of MR and fewer heart-failure related cardiac events” J Am Coll Cardiol 2014;63:2438-88. Eur J Cardiothorac Surg 2011;39:295-303. N Engl J Med 2014;370:23-32. N Engl J Med 2016;374:344-53

5. HOWEVER… Augmented leaflet tethering can be tempered by subvalvular procedures 1 A geometric disturbance requires a geometric correction MV repair approach should consider not only the mitral annulus, but also the subvalvular apparatus standard undersizing restrictive annuloplasty alone VS annular and subvalvular approach (restrictive annuloplasty + papillary muscle approximation) to investigate the relative role of papillary muscle surgery in IMR Preservation of PM function is associated with longer overall survival 2 Cardiac imaging confirmed the importance of subvalvular apparatus 3 1 Am J Cardiol 2010;106:395-401. Circulation 2012;126:2720-7. 2 JTCS 2014;148:1947-50. JTCS 2012;143:1352-5. Acta Cardiol 2013;68:271-8. 3 JTCS 2004;128:543-51. Circulation 2010;122:S29-36. JTCS 2014;148:3252-4

6. STUDY DESIGN Final evaluation after 5 years from the surgical procedure (November 2015) PMARA

7. ENDPOINTS PRIMARY ENDPOINT: left ventricular remodeling LVEDD absolute difference from baseline, over a 5 years follow up SECONDARY ENDPOINTS Changes in echocardiographic parameters (EF, recurrent moderate-to-severe MR,…) Overall mortality Major adverse cardiac and cerebrovascular events (cardiac death, stroke, reintervention, hospitalization for heart failure, NYHA class worsening) Quality of life measures (Minnesota Living with Heart Failure, 12-item Short Form Health Survey, EuroQoL 5D) Circulation 1997;96:3294-9. J Card Fail 2003;9:350-3. N Engl J Med 2009;361:1329-38

8. SURGICAL PROCEDURE PMA was performed using a 4 mm Gore-Tex tube encircling the PM bodies. Restrictive annuloplasty was performed using a Physioring (size 26 or 28 mm). Concomitant CABG was performed to achieve complete revascularization. The intraoperative goal: 25% reduction of the end-diastolic interpapillary distance compared to preoperative value (flax thread method). J Card Surg 2008;23:733-5

9. BASELINE CHARACTERISTICS RA N = 48 PMA N = 48 P value Age64.6±7.462.9±7.00.310 Previous myocardial infarction Inferior Antero-infero-posterior Antero-lateral 29 10 9 29 11 8 0.948 Ring size N° 26 Ring size N° 28 19 29 22 26 0.536 Number of grafts, mean 1 2 3 4 2.7±1.2 12 4 17 15 2.9±1.2 12 2 14 20 0.549 0.643 Double IMA28300.676 Cardiopulmonary bypass time108.1±8.4116.3±9.2<0.001 Aortic cross clamp time93.4±6.3100.8±9.9<0.001

10. LVEDD RAPMAP value Preoperative (number of patients) 61.4±3.7 (48) 62.7±3.4 (48) 0.076 1 year55.4±3.2 (38) 56.0±3.1 (40) 0.403 2 years56.3±4.1 (38) 56.4±3.6 (40) 0.909 5 years60.6±4.6 (34) 56.5±5.7 (37) 0.001 Change from baseline-0.2±2.3-5.8±4.1<0.001 Significant improvement in both groups In RA, progressive LV enlargement, values similar to pre-op PMA mantained the benefits achieved soon after surgery

11. EJECTION FRACTION Greater recovery of the LV function in the PMA group RAPMAP value Preoperative36.7±3.7%35.0±5.3%0.072 5 years39.9±3.9%44.1±6.0%<0.001 Change from baseline2.5±4.3%8.8±5.9%<0.001

12. RECURRENT MITRAL REGURGITATION Moderate-to-severe MRRAPMAP value 1 year 1 (2.6%) 3 (7.5%) 0.330 2 years 5 (13.2%) 6 (15.0%) 0.815 5 years 19 (55.9%) 10 (27.0%) 0.013 Lower incidence of recurrent MR in the PMA group

13. OVERALL MORTALITY RAPMA P value In-hospital 4 (8.3%) 3 (6.2%) 1.000 Cardiac-related 10 (20.8%) 8 (16.7%) 0.601 Overall 14 (29.2%) 11 (22.9%) 0.496 No differences in overall mortality

14. COMPOSITE CARDIAC END POINT RAPMAP value Rehospitalization17100.112 NYHA worsening20120.083 Reoperation730.181 Freedom from MACCEs was in favor of PMA in the last year of follow-up

15. MAIN FINDINGS 1)A decrease in LV dimension and an improvement in LV function in PMA, with stability of the ventricular diameters and a more effective recovery of the geometry of the MV (RA is not able to counteract or prevent the negative remodeling phenomenon occurring over time in IMR) 2)No significant differences in overall mortality and in the QoL 3)A reduced incidence of MACCEs in PMA group in the long-term (protective effect of papillary muscle surgery?) 4)A lower incidence of moderate-to-severe MR in the PMA group

16. Cardiothoracic Surgical Trials Network (CTSN) Trial Superiority of a MV replacement over its repair for recurrence of MR No significant between-group differences in LV reverse remodeling No significant differences in MACCEs, overall mortality or QoL Goldstein et al. reported a 2-year incidence of moderate-to-severe MR of 58.8%, while in our cohort it ranged between 13 and 15%. Can differences in baseline and operative characteristics account for different results ? N Engl J Med 2014;370:23-32. N Engl J Med 2016;374:344-53

17. Cardiothoracic Surgical Trials Network (CTSN) Trial N Engl J Med 2014;370:23-32. N Engl J Med 2016;374:344-53 CTSN Trial N = 251 PMA Trial N = 98 Mean age (years)69-7063-64 Myocardial revascularization74-75% 100%, complete revascularization Previous procedures 20% CABG (redo) 35% PTCA 0% Baseline ejection fraction40±11 %36±6 % Annulus size – ring size (mean difference, mm) 3 (31.0 / 27.9) 10 (39.5 / 27.1) Long-term worse LV remodeling in CTSN Trial Better long-term outcomes in PMA Trial More heterogeneous patients in CTSN Trial Higher degree of retraction Reduced short-term MR recurrence in PMA Trial

18. The “Achilles heel” of MV repair in IMR is the long-term adverse LV remodeling, which influences the geometrical relationships within the ventricle and the equilibrium between forces. Papillary muscle surgery together with complete myocardial revascularization can address these issues improving the general negative outcomes of this procedure. Direct comparison of a “complete” MV repair strategy, including papillary muscle surgery, versus chordal-sparing mitral replacement should be advocated to define the best treatment in IMR CONCLUSION

19. PERSPECTIVES PM approximation may induce a geometrical “restraint effect” on the left ventricle: towards geometry-based biomechanical formulas (Fraldi M, Nappi F)

20. Grazie per l’attenzione ! ( Thank You for Your attention ! )