Robert M. Graham
Victor Chang Cardiac Research Institute and
St Vincent’s Hospital, Sydney, Australia
Australian Health Insurance Association Conference
31 Oct - 2 Nov, 2006

1 November,
2006

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.

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

Earliest known cardiac catheterisations were performed by Hales in
1711 – inserting brass pipes through the veins and arteries into the hearts of horses.
Using the wind-pipes of geese as a connector, the brass pipes were connected to glass tubes to measure pressure – the water columns rose to >9 feet .

• 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

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

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

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

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

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

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

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

Poss et al, Science 2002

Old way of thinking =
– The heart can not repair itself
– After a heart attack, dead heart cells are not replaced

There are stem cells in the heart!

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!

Heart stem cells may multiply after a heart attack

Blood vessel stem cells are also important

• 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

Research using stem cells in humans

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)

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

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

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

Age
Sex
Body mass index
Diabetes
High cholesterol
High blood pressure
Smoking
Family history
(1 st 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

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

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