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

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

Stem Cells

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

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

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

Injected in peri-infarct tissue 3-5hrs after LAD ligation Nature 2001;410:701-705 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

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

Transfected with murine Akt by VSV retrovirus Nature Medicine 2003;9:1195-1201 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

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

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

Bone Marrow Derived Stem Cells : Vascular Injury

Bone Marrow Derived Stem Cells : Atherosclerosis

Bone Marrow Derived Stem Cells : Transplant Vasculopathy

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

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

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

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

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

Mean ~CK 800 U/L

TOPCARE-AMI: Late MRI follow up

TOPCARE-AMI: Late MRI follow up

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.

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.

Saline GM-CSF Saline GM-CSF

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

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

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

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

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