1. Department of Cardiovascular Medicine John Radcliffe Hospital, Oxford
Stem Cells
Interaction between NO and superoxide appears to be an important feature of vascular disease models. However, its importance in human atherosclerosis is unclear.
Keith Channon
Department of Cardiovascular Medicine
University of Oxford
John Radcliffe Hospital, Oxford

2. Adult Stem Cells Unique cells that are capable of self-renewal
Have the ability to differentiate through a committed lineage
Undergo further development within an adult organism v embryo
They are multi(pluri)potent v totipotent

3. Stem Cells

4. Phenotypically Characterised Adult Stem Cells
N Engl J Med 2003;349:

5. Why are Stem Cells Relevant to Interventional Cardiology?
Stem cells may offer new therapeutic approaches in cardiovascular disease
Understanding stem cell biology challenges and informs our understanding of cardiovascular disease

6. Skeletal Myoblast Cell Transplant in Ischaemic Cardiomyopathy
Multinucleate
Negative for
Connexin 43
Desmosomes
Cadherin
No integration
Menasché P et al. Myoblast transplantation for heart failure. Lancet 2001

7. Injected in peri-infarct tissue 3-5hrs after LAD ligation
Nature 2001;410:
Lin- c-kitPOS bone marrow cells from EGFP male mice to myocardium of female C57B6mouse
Injected in peri-infarct tissue 3-5hrs after LAD ligation

8. a
c-kit pos
c-kit neg
Green=Cell Nuclei
Red=Cardiac Myosin

10. Transfected with murine Akt by VSV retrovirus
Nature Medicine 2003;9:
CD117+ CD90+ CD34– MSCs from BM male rats isolated by adhesion to polystyrene, purified by immunoselection,
Transfected with murine Akt by VSV retrovirus
Permanent CAL of LAD in female rats
60 mins post CAL MSCs injected 5 peri-infarct sites

11. Engraftment does not occur in absence of MI……..

15. Conclusions
Bone marrow-derived lineage negative progenitors regenerate infarcted murine myocardium
Autologous “skeletal lineage” progenitors improve cardiac function and survive in infarction scar

16. Bone Marrow Derived Stem Cells : Vascular Injury

17. Bone Marrow Derived Stem Cells : Atherosclerosis

18. Bone Marrow Derived Stem Cells : Transplant Vasculopathy

19. Stem Cells in Human Restenosis ?
smc-actin
c-kit+
Hibbert et al. Am J Physiol 2004

20. Stem Cells in Human Restenosis ?
smc-actin
c-kit+
Hibbert et al. Am J Physiol 2004

21. Nude mice
1 day post femoral artery excision
Intracardiac medium, human µvascular ECs or EPCs

22. Endothelial Progenitor Cells- Role in Endothelial Maintenance
Cytokines
e.g. G-CSF
STATINS
EXERCISE
high blood pressure
high cholesterol / triglycerides
smoking
diabetes
infections
other
RISK FACTORS
Jonathan Hill, 2004

23. J. Hill et al. NEJM 2003; 348:

26. Mean ~CK 800 U/L

28. TOPCARE-AMI: Late MRI follow up

29. TOPCARE-AMI: Late MRI follow up

30. The STIMULATE Trial
Title Multicenter, randomized controlled study of transplantation of bone marrow-derived progenitor cells into infarct vessels of patients following an acute myocardial infarction, acutely re-vascularised by percutaneous intervention.
Principal Investigators Prof. Dr. A. M. Zeiher & J.W. Goethe, University of Frankfurt
Sponsor Cardio-Cell, Zutphen, the Netherlands (parent Cryo Cell using subsid MainGen in Frankfurt )
Monitoring CorTrial, Berlin
Objective To assess the safety and efficacy of intracoronary therapy with bone marrow-derived autologous progenitor cells with respect to improvement of myocardial function after an acute myocardial infarction treated by PTCA.
Design Multi-center,Randomized 1:1
Primary endpoint improvement of left ventricular dysfunction at rest and during Dobutamine stress, assessed by echocardiography at 4 months.

31. THE PRIMATIVE Trial Leicester
Percutaneous Randomised Infusion of Marrow Aspirate To Improve Ventricular Efficiency
Principal Investigators Tony Gershlick, Nilesh Samani et al.
Objective Assess the safety and efficacy of intracoronary therapy with bone marrow-derived autologous progenitor cells delivered at salvage PCI (DES) after acute MI, either early or late.
Design Single-center, Randomized, Placebo-Controlled n=150
Primary endpoint improvement of left ventricular function, assessed by echocardiography and cardiac MRI at 4 months, and clinical events, up to 5 years.

32. Saline
GM-CSF
Saline
GM-CSF

34. EPC Colony-Forming Capacity Following G-CSF
J. Hill et al. JACC 2005; in press

35. G-CSF and In-stent Restenosis after MI Kang et al. Lancet 2004
Patients undergoing PCI with stenting of culprit artery following MI (3 days to 9 months) randomized to G-CSF ± apheresis / IC infusion, control
No AE’s associated with G-CSF treatment
At 6 month F/U, improved treadmill time, LVEF, SPECT perfusion in cell infusion group
In-stent restenosis determined in 7/10 G-CSF treated patients, 0/1 control
Study terminated

36. Isolation of EPCs for Stent Delivery
vWF
Flk-1
LDL-Uptake
Shirota et al. Biomaterials 2003

39. Stem Cells in Interventional Cardiology
vascular disease risk, biology, drug therapy
cell therapy for post-MI repair
cell therapy in PCI

40. Future Directions Circulating or Bone Marrow Progenitor Cells?
Harvest or not, which subset?
Statins
Cytokine stimulation to release- e.g. CXCR4, new drugs
Circulating / Bone Marrow progenitor cells clinical trials- need to be blinded, placebo controlled, with hard end points
Understanding mechanisms remains critical to evaluating and targeting real benefits