1. www.europcronline.com/ Stem Cell Therapy & CV Innovations Madrid, April 23 - 24, 2009 Next Steps in Heart Replacement My Clinical View William Wijns Cardiovascular Center, Aalst (B)

2. Next Steps in Heart Replacement My fundamental view My preclinical view My translational view My clinical view My global view Stem Cell Therapy and CV Innovations # 6: Closing Session What are the unmet needs ? What are the unmet needs ?

3. STEM CELL THERAPY END-POINTS and “MECHANISMS AT WORK” Target organ – heart Target organ – heart Remote Homing Remote Homing Arrhythmias Arrhythmias Coronary vasculature Coronary vasculature CELL PRODUCT Type Type Source and harvest Source and harvest Function and number Function and number CELL PROCESSING CELL PROCESSING CELL DELIVERY PATIENT Disease Disease Risk Profile Risk Profile Bone Marrow Bone Marrow Clinical Needs for CV Cell Therapy Many Factors to be Considered From J. Bartunek et al

4. Next Steps in Heart Replacement My clinical view My fundamental view My preclinical view My translational view My global view

5. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /...

6. Function of Stem/Progenitor Cells in AMI Bone marrrow cells or circulating progenitor cells  Improve neovascularization  Differentiate to cardiac myocytes (?)  Release paracrine factors  Influence LV remodeling Bone marrrow cells or circulating progenitor cells  Improve neovascularization  Differentiate to cardiac myocytes (?)  Release paracrine factors  Influence LV remodeling Vascularization  Apoptosis  Vascularization  Apoptosis  Paracrine factors Cardiac Regeneration Cardiac Regeneration Acute Infarction LV- Dilatation   Adapted from A. Zeiher et al

7. Abdel-Latif, Arch Intern Med 2007 Overall modest efficacy but clinical safety demonstrated over 1 to 2 years period Clinical Trials with Adult Hematopoietic Stem Cells Only bad cases may benefit (ejection fraction < 40 %) Only bad cases may benefit (ejection fraction < 40 %)

8. STENT for LIFE STEMI reperfusion treatment in Europe

9. STENT for LIFE Nationwide „thrombolytic strategy“ for STEMI results in 46% untreated patients ! % from all STEMI

10. STENT for LIFE Reperfusion strategy paradox Most people think that thrombolysis is a kind of treatment widely available for patients everywhere, while p-PCI is limited in its availability The opposite is true: far more patients receive reperfusion treatment in countries with low use of thrombolysis and high use of p-PCI !

11. STENT for LIFE In-hospital mortality of all STEMI pts in countries with p- PCI dominance vs countries with thrombolysis dominance %

13. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ?

14. Mortality of Acute CAD decreases, Heart Failure population increases Time MORTALITY Streptokinase GISSI 1, 1986 tPA GUSTO-I, 1995 Balloon angio 1977 Stenting 1987

15. A true challenge Cardiovascular disease in Europe

16. Functionality vs Lack of Proper Signalling Damaged adult heart is devoid of embryonic signalling and may fail to recapitulate necessary milieu to stimulate myocardial specification resulting in limited functionality and unwanted signalling/differentiation Olson, Nat Medicine 2004; Chien, Nature 2004; Wang, J Thorac Cardiovasc Surg 2001; Yoon, Circulation 2004; Befhar, JMCC 2007 From J Bartunek

17. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++

18. Clinical Needs for CV Cell Therapy End-stage Heart Disease New hearts for old and new needs Cardiac replacement Bridge? Destination? Both? Artificial hearts and biosensors Xenotransplant

19. Current treatments are palliative only and costly * cost /year of life and /patient (US $) American College of Cardiology / American Heart Association TREATMENTS COST (USD) * NYHA Class IACE inhibitor Diuretics 15,000-45,000 NYHA Class II + Beta-blocker ICD 39,000-64,000 NYHA Class III + Digoxin Bi-ventricular pacers, ICD 65,000-85,000 NYHA Class IV + Hemodynamic Support Mechanical Assist Devices Transplant 250,000-310,000

20. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++ +

21. Conductance Arteries <500 µ PaPaPaPa 100 MICRO Abnormal Resistance in Mildly Atherosclerotic Coronary Arteries >500 µ Resistance Arteries MACRO Microvasculature

22. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient (PVD?) Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++ + ▼

23. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++ + ▼ ?

24. Circulation 2000;101:1899-1906 Prognostic Impact of Coronary Vasodilator Dysfunction on Adverse Long-Term Outcome of Coronary Heart Disease Volker Schächinger, MD; Martina B. Britten, MD; Andreas M. Zeiher, MD From the Department of Internal Medicine IV, Division of Cardiology, J.W. Goethe University, Frankfurt, Germany

25. Euro Heart Survey ESC CVD in Europe 2006 Ageing of the Population

26. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++ + ▼ ? ++

27. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++ ++ ▼ ? ++ ?

28. Isolation of "side population" progenitor cells from healthy arteries of adult mice Sainz J, Al Haj Zen A, Caligiuri G, Demerens C, Urbain D, Lemitre M, Lafont A. Arterioscler Thromb Vasc Biol. 2006 Feb;26(2):281-6. Epub 2005 Nov 23. Gingival fibroblasts inhibit MMP-1 and MMP-3 activities in an ex-vivo artery model Naveau A, Reinald N, Fournier B, Durand E, Lafont A, Coulomb B, Gogly B. Connect Tissue Res. 2007;48(6):300-8.

29. Clinical Needs for CV Cell Therapy (First) Acute Myocardial Infarction Chronic Ischemic Heart Failure End-stage Heart Disease Non-revascularisable Patient Non Ischemic Cardiomyopathy Endothelial dysfunction Arrhythmias & Conduction defects A A A and aortic disease... /... ? +++ ++ ▼ ? ++ ? ▲

30. 5 million years 50 years 5 million years 50 years

31. CVD in Europe 2006 Ageing of the Population

32. Courtesy P. Puska Disease burden

33. Next Steps in Heart Replacement My fundamental view My preclinical view My translational view My clinical view My global view Stem Cell Therapy and CV Innovations # 6: Closing Session What are the solutions for the ever growing unmet needs ? Disruptive technologies What are the solutions for the ever growing unmet needs ? Disruptive technologies

34. www.europcronline.com/ Conflict of Interest for William Wijns I disclose the following financial relationships: Consulting Fees: on my behalf go to the Cardiovascular Research Center Aalst Consulting Fees: on my behalf go to the Cardiovascular Research Center Aalst Contracted Research: between the Cardiovascular Research Center Aalst and several pharmaceutical and device companies Contracted Research: between the Cardiovascular Research Center Aalst and several pharmaceutical and device companies Ownership Interest: Cardiovascular Research Center Aalst is co-founder of Cardio³BioSciences, a start-up company focusing on cell-based therapies Ownership Interest: Cardiovascular Research Center Aalst is co-founder of Cardio³BioSciences, a start-up company focusing on cell-based therapies