1. Transcatheter Mitral Valve Implantation
Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial Interest /arrangement or affiliation with the organization (s) listed below
Research Funding: Abbott, Inc.
Edwards LifeSciences, Inc.
Speaking Honoraria: Edwards LifeSciences, Inc.
Consultant / Equity: Endovalve, Inc.
Discussion will include unapproved and off-label devices, procedures, and indications
Howard C. Herrmann, MD Professor of Medicine Director, Interventional Cardiology and Cardiac Catheterization Laboratories University of Pennsylvania Medical Center

2. Anatomic Classification for Transcatheter Therapy
Leaflet
Edge-to-edge repair
Space occupier
Abbott
Cardiosolutions
Annulur
dilatation
Indirect via cor sinus
Direct - cinching
- energy-mediated
- rings
Card. Dimen., Viacor
Mitralign, GDS
QuantumCor, ReCor
Mitral Solutions, MiCardia, Millipede
Chordae
Transapical replacement
Neochord
Ventricular
Remodeling
Coapsys, Mardil
Combination
Replacement
Endovalve, CardiaQ
Modified from Chaim and Ruiz, JACC Interv (in press)

3. Coronary Sinus Devices: Phase 1/FIM Efficacy
Edwards Monarc
Card. Dimen. Carillion
Viacor
PTMA
Improvement in quant. measures MR
~30%
MR grade
60% 1 grade
~1 grade
NYHA class
~ 1 class
Annular dimension (cm)
10%
MR reduction is modest
Likely less than achievable with surgery
Will this translate into sufficient improvement in symptoms and/or LV remodeling to justify the procedure?
Can “super-responders” be identified prospectively?

4. Concerns Relative to Edge-to-Edge Repair
Theoretical Concerns
Non-anatomic repair – probably not an issue, but clip repair is not identical to Alfieri stitch repair
May cause mitral stenosis – probably not
Will need to select patients carefully (? 1 in 10)
May need a ring for long-term benefit
Only true for a subset of patients?
Functional vs. degenerative
Technical complexity of procedure
Safety
Good, not perfect (6% partial detachments, 1% stroke, 1% death ITT)
Surgery required in >20% by 1 year
Late surgical repair feasible, but how late and with lower repair rate
Efficacy
MR improvement for sure, but not as good as surgery (>50% > 2+ MR at 1 year in per protocol analysis)
LV remodeling occurs, but not as much as with surgery?
Do we need longer f/u and randomized data in high risk and functional?

5. Transcatheter Mitral Valve Implantation
Increasing evidence that percutaneous approaches are more limited than surgical techniques and unlikely to achieve equal efficacy
Efficacy and risks of surgical mitral valve replacement are well understood
Better reduction in MR than repair
Not all patient populations, disease etiologies, anatomical variations will be compatible with repair
Risks equivalent to repair in functional etiology, higher-risk, older patients with current generation of bioprostheses and complete valve- sparing operations
However surgical MVR has significant morbidity and mortality due to risks of incision and CPB
For these reasons it is important to offer clinicians and patients a less invasive, valve-sparing means of performing a MV replacement 8

6. Evaluation of Outcomes Following Mitral Valve Repair vs Replacement in Severe Ischemic MR (NIH Sponsored CT Surgery Network Research Group Study)
250 subjects with severe MR (ERO > 0.4 cm2) (+ CABG)
MV repair (annuloplasty w subvalv procedure if severe tethering)
MV replacement with complete subvalvular preservation
1° endpoint = LV remodeling (LVESVI) at 12 mos
Statistical power 90% to detect 15 ml/m2 diff in LVESVI between groups (15% additional reduction after 20%)
2° endpoint = mortality, functional status, QOL, etc.
Highlights
High recurrence rate of severe MR after annuloplasty alone
Need to address subvalvular changes with repair in IMR
Lack of data comparing replacement to repair in other than observational or case series with mixed patient populations

7. Mitral Pericardial Bioprosthesis (Edwards PERIMOUNT)
> 70 yrs
> 65 yrs
> 60 yrs
< 60 yrs

8. Mehta R. H. et al.; Ann Thorac Surg 2002;74:1459-1467
Mortality by age for low-risk, medium-risk, and high-risk categories of patients undergoing surgical mitral valve replacement
STS Database: 31,688 pts
Use of bio-prostheses:
20% (<50 yrs) to 80% (>80 yrs)
Mortality risk increased with age:
4.1% (<50 yrs) to 17.0% (>80 yrs)
Morbidity (stroke, prolong vent, reop, renal failure, sternal infection) increased with age:
13.5% (<50 yrs) to 35.5% (>80 yrs)
Multivariable predictors M&M:
Age, hemo instability, NYHA IV, renal failure, CABG
> 10% Mortality
Mehta R. H. et al.; Ann Thorac Surg 2002;74:

9. Transcatheter Mitral Valve Implantation With Stent Prostheses
D. Paniagua 1
Acute human insertion of aortic prosthesis in mitral position
G. Lutter 2
Transapical off-pump insertion porcine prosthesis self-expanding nitinol stent
Acute success but 7/8 pigs died early due to:
Paravalvular leaks
Suboptimal positioning
Failure of fixation
Subsequent report of fixation to 60 min (1 death, multiple attempts to position)
Perc Cardiovasc Solutions (S. Thambar 1)
CardiAQ
1 Personal communication
2 Lozonschi et al, Ann Thorac Surg 2008;86:745; EJCTS 2009

10. Transcatheter MV Implantation: Challenges
Delivery
Fold/compress, size (larger than aortics)
Fixation
More complex structure
No calcium to grab radially
Not a round valve, particularly when diseased and less pliable
Orientation may be important
Seal
Paravalvular leak likely less well tolerated than aortic (hemolysis)
Function
LVOT obstruction a concern
Need to preserve the subvalvular apparatus

11. Endovalve Inc.
Endovalve Inc is a cardiovascular device company developing a mitral valve replacement system designed initially for insertion during a minimally invasive surgical (MIS) procedure
The proprietary Endovalve system is designed to allow for a complete mitral valve replacement without the risks and complications usually associated with open-heart surgery, avoiding both sternotomy and cardio-pulmonary bypass.
Clinical advantages of this approach include:
Reduction in MR as good as surgery
Takes advantage of improving durability of bioprosthetic leaflets
Fully valve-sparing (similar to repair)
Initially based on patented technology from the Univ of PA, our platform will allow for later development of a percutaneous system utilizing the same valve design.

12. Transcatheter Mitral Valve Implantation Engineering Prototype – Sheep Implant
No MR at 6 hours post CPB
Mean transmitral gradient = 2 mm Hg
No LVOT gradient 16

13. Conclusions
Minimally-invasive surgical (MIS) insertion of a foldable bio-prosthetic mitral valve is feasible
Advantages of this approach include:
Avoidance of the complications of conventional cardiac surgery
Cardiopulmonary bypass
Sternotomy
Fully valve sparing
MR reduction equivalent to surgical valve replacement
Demonstrated unique product design and function
Current focus is on improving delivery efficiency for both MIS and fully percutaneous approaches
Animal trials with improved designs planned 2011