Www.europcronline.com/ Stem Cell Therapy & CV Innovations Madrid, April 23 - 24, 2009 Next Steps in...

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Stem Cell Therapy & CV InnovationsMadrid, April 23 - 24, 2009

Next Steps in Heart ReplacementMy Clinical View

William WijnsCardiovascular Center, Aalst (B)

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 ?

STEM CELLSTEM CELL

THERAPY THERAPY

END-POINTS andEND-POINTS and

““MECHANISMS AT WORK”MECHANISMS AT WORK”• Target organ – heartTarget organ – heart• Remote HomingRemote Homing• ArrhythmiasArrhythmias• Coronary vasculatureCoronary vasculature

CELL PRODUCTCELL PRODUCT• TypeType• Source and harvestSource and harvest• Function and numberFunction and number

CELL PROCESSINGCELL PROCESSING

CELL DELIVERYCELL DELIVERY

PATIENTPATIENT• Disease Disease • Risk Profile Risk Profile • Bone MarrowBone Marrow

Clinical Needs for CV Cell TherapyMany Factors to be Considered

From J. Bartunek et alFrom J. Bartunek et alFrom J. Bartunek et alFrom J. Bartunek et al

Next Steps in Heart Replacement


• My fundamental view



• My global view

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• . . . / . . .

Function of Stem/Progenitor Cells in AMIFunction of Stem/Progenitor Cells in AMI

Bone marrrow cells or circulating

progenitor cells Improve neovascularizationDifferentiate to cardiac myocytes (?)Release paracrine factorsInfluence LV remodeling

Bone marrrow cells or circulating

progenitor cells Improve neovascularizationDifferentiate to cardiac myocytes (?)Release paracrine factorsInfluence LV remodeling

Vascularization Apoptosis

Vascularization Apoptosis

Paracrine factorsParacrine factors

CardiacRegenerationCardiacRegeneration

Acute InfarctionAcute Infarction

LV- DilatationLV- DilatationAdapted from A. Zeiher et alAdapted from A. Zeiher et alAdapted from A. Zeiher et alAdapted from A. Zeiher et al

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 %)

STENT for LIFE

STEMI reperfusion treatment in Europe

92

17

86

0

14

75

12

13

75

5

20

70

20

10

72

3

25

70

20

10

70

15

15

66

8

26

66

10

24

59

14

27

49

15

36

45

40

15

45

15

40

30

35

35

30

26

44

35

35

30

24

55

21

19

44

37

19

33

48

23

25

52

9

41

50

8

29

63

5

45

50

5

10

85

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

CZ SLO NO DK BE PL CH HR SE HU DE IL FIN IT ES SK AT UK PO SRB BG GR TR RO RU

P-PCI TL No reperfusion

STENT for LIFE

Nationwide „thrombolytic strategy“ for STEMI results in 46% untreated patients !

20

46

0

5

10

15

20

25

30

35

40

45

50

No reperfusion used

Countries with p-PCIdominance

Countries withthrombolysisdominance

% from all STEMI

STENT for LIFE

Reperfusion strategy paradox

• Most people think that thrombolysis is a kindof 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 !

STENT for LIFE

In-hospital mortality of all STEMI pts in countries with p-PCI dominance vs countries with thrombolysis dominance

6,5

10,3

0

2

4

6

8

10

12

All STEMI mortality

PCI countries

TL countries

%



?

Mortality of Acute CAD decreases, Heart Failure population increases

Time

MORTALITY

StreptokinaseGISSI 1, 1986

tPAGUSTO-I, 1995

Balloon angio1977

Stenting1987

A true challengeCardiovascular disease in Europe

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/differentiationOlson, Nat Medicine 2004; Chien, Nature 2004; Wang, J Thorac Cardiovasc Surg 2001; Yoon, Circulation 2004; Befhar, JMCC 2007

From J BartunekFrom J BartunekFrom J BartunekFrom J Bartunek



?

+++


• End-stage Heart Disease

New hearts for old and new needs

Cardiac replacement

Bridge? Destination? Both?

Artificial hearts and biosensors

Xenotransplant

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 I ACE inhibitor

Diuretics15,000-45,000

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



?

+++

+

Conductance ArteriesConductance Arteries

<500 µ<500 µ

PPaa

100100

MICROMICRO

Abnormal Resistance in Mildly Atherosclerotic Coronary ArteriesAbnormal Resistance in Mildly Atherosclerotic Coronary Arteries

>500 µ>500 µ

Resistance ArteriesResistance Arteries

MACROMACRO

MicrovasculatureMicrovasculature


• (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• . . . / . . .

?

+++

+

▼



?

+++

+

▼

?

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

POPULATION AGED 65+ YEARS

12 to 168 to 124 to 8

16 to 20No data

Percentage

Proportion of 65+ years of age

5

10

15

20

1980 1985 1990 1995 2000 2005

0

10

15

20

% 65+

▬ European Region▬ EU-10

▬ European Union▬ EU-15

▬ CIS

Euro Heart Survey ESC

CVD in Europe 2006Ageing of the Population



?

+++

+

▼

?

++



?

+++

++

▼

?

++

?

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.



?

+++

++

▼

?

++

?

▲

5 million years 50 years 5 million years 50 years

159

141822273135404448535761667074798388

Age pyramid for Europe in 2004Age

Men Women

4 3 2 1 0 1 2 3 4

Numbers per million

90+

85

80

75

70

65

60

55

50

45

40

35

30

25

20

15

10

5

0 159

141822273135404448535761667074798388

Age pyramid for Europe in 2050Age

Men Women

4 3 2 1 0 1 2 3 4

Numbers per million

90+

85

80

75

70

65

60

55

50

45

40

35

30

25

20

15

10

5

0

CVD in Europe 2006Ageing of the Population

Courtesy P. PuskaCourtesy P. Puska

Diseaseburden

Next Steps in Heart Replacement• My fundamental 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

www.europcronline.com/

Conflict of Interest for Conflict of Interest for William WijnsWilliam Wijns

I disclose the following financial relationships:I disclose the following financial relationships:

Consulting Fees: on my behalf go to the Cardiovascular Research Consulting Fees: on my behalf go to the Cardiovascular Research Center AalstCenter Aalst

Contracted Research: between the Cardiovascular Research Center Contracted Research: between the Cardiovascular Research Center Aalst and several pharmaceutical and device companies Aalst and several pharmaceutical and device companies

Ownership Interest: Cardiovascular Research Center Aalst is co-founder Ownership Interest: Cardiovascular Research Center Aalst is co-founder of Cardio³BioSciences, a start-up company focusing on cell-based of Cardio³BioSciences, a start-up company focusing on cell-based

therapiestherapies

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