MITRALIGN: Direct Annuloplasty CRT 2010 Washington DC, January 21, 2010 MITRALIGN: Direct Annuloplasty Device Evolution, Technique and Clinical Trial Update Eberhard Grube, MD, FACC, FSCAI St.Elisabeth Hospital, Heart Center Rhein-Ruhr, Essen, Germany Instituto Cardiologico Dante Pazzanese, São Paulo, Brazil

Eberhard Grube, MD DISCLOSURES Consulting Fees Honoraria Abbott Vascular, Boston Scientific Corporation, Cordis, a Johnson & Johnson Company, Medtronic CardioVascular, Inc. Honoraria Biosensors International , Boston Scientific Corporation, Medtronic CardioVascular, Inc Ownership Interest (Stocks, Stock Options or Other Ownership Interest) Biosensors International , Medtronic CardioVascular, Inc. I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation. I intend to reference off-label use of stents and valve prosthesis.

Disclosure Eberhard Grube, MD Mitralign: C Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Physician Name Company/Relationship Eberhard Grube, MD Mitralign: C Key G – Grant and or Research Support E – Equity Interests S - Salary C – Consulting fees, Honoraria R – Royalty Income I – Intellectual Property Rights SB – Speaker’s Bureau O – Ownership OF – Other Financial Benefits‘ 3

MITRALIGN Concept Surgical approaches for treatment of FMR are focused on size reduction of the mitral valve annulus. A relatively small (1 cm) plication of the posterior annulus can normalize the septo-lateral dimension and reduce MR. Mitralign concept emulates suture annuloplasty. Retrograde LV approach Surgical pledgets are delivered percutaneously through the posterior annulus Plicate the annulus

Trident Design 12.5 Fr. Guide Catheter Steerable catheter provide ventricular access for all catheters Steerable catheter access mitral annulus at P2 center deliver crossing wire (RF) to penetrate the annulus A triple lumen catheter (Trident) advanced over the P2 crossing wire provide positioning of P1 and P3 locations deliver P1 and P2 crossing wires to penetrate the annulus Pledget delivery catheter tracked over a crossing wire through the annulus deliver the pledget Plication catheter plicate by exerting tension via the sutures deploy a stainless steel lock to lock the three sutures Suture cutter cut the sutures following deployment of the lock

Concept Annular Plication Mitralign Concept Interventional surrogate of surgical suture annuloplasty Anchors are placed along the posterior annulus Plication using these anchores, herewith reducing the circumference which restores leaflet coaptation P3 P1 P2 Concept Annular Plication 6

First in Man Experience Paraguay Pre-Plication Final Implant P1 P2 P3 P1 P2 P3 Baseline 12 months FU MR 3+ 2+ EDV (ml) 168 115 ESV (ml) 85 MVA (cm2) 4.0 2.83 NYHA III I

Trident Concept First in Man Experience Four patients implanted in Paraguay by Dr. A. Ebner 3 patients with all 3 pledgets 1 patient with 2 pledges only Surgical pledgets can be delivered through the mitral annulus Mitralign approach can be developed further Difficult to manage 3 components (wires, pledgets and sutures) at the same time: Simpler design is needed

New MITRALIGN Design Bident Catheter A double lumen catheter (Bident) to be advanced over a crossing wire and to provide positioning of a pair of wires Two pairs of pledgets to be delivered in P1-P2 location P2-P3 location Span of the bident catheter available: 1.4 cm or 1.7 cm.

MITRALIGN Bident Design Permanent Implants Atrial Side Ventricle Side Two plications in two locations: P1-P2 and P2-P3 Minimum permanent implants 4 surgical pledgets 2 locks to lock the sutures after plication

Mitralign System Steerable Guide Steerable Wire Delivery Catheter Crossing Wire Translation Catheter Pledget Delivery Catheter Plication Lock and Cut Catheter

Bench Test: Bident vs. Trident Before Plication After Plication 20 mm 16 mm TRIDENT 27mm 26 mm 20 mm 12 mm BIDENT 27 mm 22 mm Bident 2x2 plication outperforms Trident plication

Pre-Clinical Study: Bident MITRALIGN Bident Design simplifies the procedure.

Normal Healing Response 30 Days After Implantation

30-Day Histology

Finite Element Analysis: Trident vs Bident Model Initial Position Plication TRIDENT BIDENT Model SL distance (mm) CC-distance (mm) MVA (cm2) Baseline 27.6 43.1 9.50 TRIDENT plication 26.6 44.4 8.30 BIDENT– 2x2 plication 23.5 39.9 7.43 Bident 2x2 plication outperforms Trident plication

Finite Element Analysis Selecting Bident Location Control Placement Plication MR due to annulus dilatation Intermediate placement of pledgets in P2/P1 and P2/P3 seems to be the best Plication causes an anterior displacement of the posterior wall of 5-10 mm

Mitralign FIM Studies South America and Europe Phase I (Trident) Phase II (Bident) Device optimization in Paraguay Limited number of implanted patients (n=4) One patient with complete FU at 1 year Significant changes in the MPAS Feasibility and safety of Bident MPAS (optimized design) 12 patients to be enrolled at 4 sites Echo Core Lab Primary objective: - to assess the safety and feasibility of MPAS for treatment of FMR Primary enpoint: - Device related NACE (net adverse clinical events) at 30 days. Device-related NACE include: Death, MI, Cardiac tamponade, Cardiac surgery, Stroke

Bident FIM Study Clinical Sites Study PI: Eberhard Grube, MD Study sites and Site PIs St.Elisabeth Krankenhaus,Heart Center Rhein-Ruhr Dr. E. Grube Helios Heart Center, Siegburg, Germany: Dr. L. Buellesfeld Asklepios Klinik St. Georg, Hamburg, Germany: Dr. K.H. Kuck Dante Pazzanesse Cardiology Center, Sao Paulo, Brazil: Drs. A. Abizaid, C. Esteves, E. Grube Klinikum-Oldenburg, Oldenburg, Germany: Dr. A. Elsaesser Echo Core Lab MedStar, Washington , DC, USA Dr. Neil Weissman

Inclusion Criteria Patient is ≥18 years old Functional Mitral Regurgitation ≥ 2+ NYHA Class: II-IV EF% ≥ 30% Mitral plane to apex dimension ≥ 5 cm Structurally normal mitral valve No significant calcification No thrombus in LV or LA

Conclusions Mitralign Percutaneous Annuloplasty System is emerging technology for direct annuloplasty. First experience with the Trident System was promising but change in design concept was needed. To simplify the procedure To possibly improve outcomes Safety and feasibility of the new Bident System will be studied in the new FIM study in Germany and Brazil.

Thank you for your attention !