1 November, 2006

1. Stem Cells for Heart Disease: hype or hopeRobert M. GrahamVictor Chang Cardiac Research Institute andSt Vincent’s Hospital, Sydney, AustraliaAustralian Health Insurance Association Conference31 Oct - 2 Nov, 2006

3. 1 November, 2006

4. Cardiology – where have we been?

5. Cardiology: Where have we been? • In ~ 400B.C., the time of Hippocrates, air and water were pushed through hollow reeds or brass pipes into the aortas of cadavers in an attempt to understand the function of the heart valves. • In 1651 Harvey inserted tubes into cadavers and proved, contrary to popular opinion, that blood in the veins flowed up to the lungs, and not down into the legs.

6. Cardiology: Where have we been? • Wren delivered the first injection into a vein of a living subject (a dog) in 1665 • Major delivered the first injection into the vein of a living human in 1667 • Also in 1667, Lower used the first catheter - a man made tube inserted into the body to transfuse blood from a sheep to a human

7. Earliest known cardiaccatheterisations wereperformed by Hales in1711 – inserting brasspipes through the veinsand arteries into thehearts of horses. Using the wind-pipes ofgeese as a connector,the brass pipes wereconnected to glass tubesto measure pressure –the water columns roseto >9 feet.

8. The first human catheterisation • Werner Forssmann (1904-79) • As a 25yo medical resident wanted to give drugs directly to the heart • Superiors “horrified” – thought that any invasion of the heart would be fatal – refused to allow this research • Practiced passing bladder catheters into the hearts of cadavers • “Gained the trust” of Gerda Ditzen, a surgical nurse, who had access to the necessary equipment

9. The first human catheterisation • In July of 1929, Ditzen (the surgical nurse) agreed to permit Forssmann to perform the first human catheterisation on her • Forssmann secured her to the operating table • He then put local anaesthetic in his own forearm and passed a bladder catheter to its full length of 65cm up his own arm • He then released the angry nurse and together they walked to the radiology department (up the stairs!) and made medical history

11. The first human catheterisation • Bitter criticism followed – Forssmann described by peers as “mentally deficient” • Fired by his superior the same day, and told “such methods are fit for a circus, but not for a respected hospital” • Abandoned cardiac research within 2 years, finally becoming a urological surgeon • Awarded the 1956 Nobel prize with other cardiac poineers, Cournard and Richards

12. On February 12th 1974,Andreas Gruentzigperformed the first balloon dilation of a human leg artery, and in 1977 this was then done in the human heart.

14. Other important recent advances in cardiology • Coronary artery bypass surgery • Awareness of the importance of diet, smoking (not!), lifestyle and exercise • Medical therapies – aspirin, blood pressure lowering drugs, cholesterol lowering tablets etc. • Coronary care units • Cardiac transplantation

15. Cardiology – where are we going?Stem cell research – future directions for heart disease treatment

16. Prometheus, who was damned to be chained to Mount Caucasus for 30,000 years. Every day an eagle would come down and pick his liver, and the next day it would have regenerated. The hound of Zeus, the tawny eagle, …feasting on thy liver Till he hath gnawn it black. - Aeschylus, Prometheus Bound

17. Muscle, skin, vessel Stem cell and divides Muscle, skin, vessel

18. Poss et al, Science 2002

19. Are there stem cells in the heart? Old way of thinking = • The heart can not repair itself • After a heart attack, dead heart cells are not replaced

20. There are stem cells in the heart!

21. What do heart stem cells do? • Human heart contains ≈ 5,000,000,000 cells • 3,000,000 cardiac cells become worn out and die each day • The heart would disappear in ≈ 4 - 5 years if these cells were not replaced!

22. Heart stem cells may multiply after a heart attack

23. Blood vessel stem cells are also important

24. Heart andblood vesselstem cells • We all have them • They probably help to fix everyday wear-and-tear • Heart stem cells try to fix things after a heart attack – but don’t do enough! • Our job is to find out why they don’t do much after a heart attack and see what helps them do more

25. Research using stem cells in humans

27. Research using stem cells in human hearts • Already over 500 patients around the world have had stem cell therapy to the heart • Many cell types have been used • Bone marrow • Muscle stem cells • Blood vessel stem cells • Many different heart problems have been treated • Days after a heart attack • Years after a heart attack • Reduced pumping of the heart (never had a heart attack)

28. POSITIVE BORDERLINE POSITIVE NEGATIVE NEGATIVE

29. Stem cell trial at St Vincent’s Hospital and The Victor Chang Cardiac Research InstituteGranulocyte-colony stimulating factor (G-CSF) and intra-coronary endothelial progenitor cell (EPC) infusion in patients with chronic refractory ischaemic heart disease

30. The stem cell team Clinical trial at SVH and VCCRI • Investigators David Muller Peter Macdonald Michael Feneley Neil Jacobs Helen Tao Andrea Herbert David Ma John Moore Sam Milliken Anthony Dodds Judy Freund Lyn Chan Silviu Itescu Robert Graham • Data and Safety Monitoring Board Roger Allan John Rasko Vivian Fernandez VCCRI cardiac stem cell lab Richard Harvey Joan Li Corey Heffernan Owen Prall Ish Ahmed Robert Graham

31. G-CSF • Typically used for bone marrow donation or transplantation • Given by daily skin injection for 3-5 days • Stimulates bone marrow and causes release of stem cells into the blood Normal BM BM after 5 days G-CSF

36. Age Sex Body mass index Diabetes High cholesterol High blood pressure Smoking Family history (1st degree relative < 55 male or < 65 female) Number of bypass operations Number open bypass grafts Number of open heart arteries Pumping ability of the heart (LVEF) Number of cardiac tablets per day 62 ± 9.0 (36 - 74) Male = 18/20, female = 2/20 29.8 ± 4.4 (22.1 - 39.2) 3/20 20/20 18/20 17/20 ex, 0/20 current 15/20 1.6 ± 0.7 (1 - 3) 1.5 ± 1.0 (0 - 4) 0.7 ± 0.9 48.7 ± 10.3% (30 - 65%) 8.7 ± 1.4 Data presented as mean ± SD (range), or number of patients/20

37. Final trial results and future directions Safe Less chest pain Less use of medications to get rid of chest pain Exercise time on the treadmill improved Quality of life improved On the basis of this small study of 20 patients, and with support from MBF, we are already in the advanced planning stages for a larger study

38. Stem cell research – future directions for heart disease treatment • Important new knowledge about stem cells and the heart and vessels • It is definitely possible to put stem cells into the human heart • Over 500 patients have already had this around the world in research studies • Although stem cells are exciting, we have a long way to go! • It took over 200 years from the first horse catheterisation in 1711 until the first human catheterisation in 1929 • It’s only taken <5 years since heart stem cells were discovered to do the first human studies