The document discusses stem cells and their relevance to interventional cardiology. It describes how adult stem cells are unique cells capable of self-renewal and differentiation. Understanding stem cell biology can inform our understanding of cardiovascular disease, and stem cells may offer new therapeutic approaches. The document then reviews several studies that have transplanted various types of stem cells into animal models of heart disease or in human clinical trials of heart attack patients to explore the potential benefits.

1. Stem Cells Keith Channon Department of Cardiovascular Medicine University of Oxford John Radcliffe Hospital, Oxford For more slides click here DOWNLOAD THIS SLIDE

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. N Engl J Med 2003;349:570-82. Phenotypically Characterised Adult Stem Cells

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

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

7. Lin - c- kit POS bone marrow cells from EGFP male mice to myocardium of female C57B6 mouse Injected in peri-infarct tissue 3-5hrs after LAD ligation Nature 2001;410:701-705

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

10. 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 Nature Medicine 2003;9:1195-1201

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 µ vascular ECs or EPCs

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

23. J. Hill et al. NEJM 2003; 348:593-600

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 P ercutaneous R andomised I nfusion of M arrow A spirate T o I mprove V entricular E fficiency 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. Shirota et al. Biomaterials 2003 vWF Flk-1 LDL-Uptake Isolation of EPCs for Stent Delivery

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